2, 7-naphthyridine derivatives

ABSTRACT

2,7-Naphthyridine containing squaric acids of formula (1) are described:  
                 
 
     wherein  
     Ar 1  is an optionally substituted 2,7-naphthridin-1-yl group;  
     L 2  is a covalent bond or a linker atom or group;  
     Ar 2  is an optionally substituted aromatic or heteroaromatic chain;  
     Alk is a chain —CH 2 CH(R)—, —CH═C(R)—,  
                 
 
      in which R is a carboxylic acid (—CO 2 H) or a derivative or biostere thereof;  
     R 1  is a hydrogen atom or a C 1-6 alkyl group;  
     L 1  is a covalent bond or a linker atom or group;  
     Alk 1  is an optionally substituted aliphatic chain;  
     n is zero or the integer 1;  
     R 2  is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloalphatic, heteropoly-cycloaliphatic, aromatic or heteroaromatic group;  
     and the salts, solvates, hydrates and N-oxides thereof.  
     The compounds are able to inhibit the binding of integrins to their ligands and are of use in the prophylaxis and treatment of immuno or inflammatory disorders or disorders involving the inappropriate growth or migration of cells.

[0001] This invention relates to a series of 2,7-naphthyridinederivatives, to compositions containing them, to processes for theirpreparation, and to their use in medicine.

[0002] Over the last few years it has become increasingly clear that thephysical interaction of inflammatory leukocytes with each other andother cells of the body plays an important role in regulating immune andinflammatory responses [Springer, T. A., Nature, 346, 425, (1990);Springer, T. A., Cell, 76, 301, (1994)]. Specific cell surface moleculescollectively referred to as cell adhesion molecules mediate many ofthese interactions.

[0003] The adhesion molecules have been sub-divided into differentgroups on the basis of their structure. One family of adhesion moleculeswhich is believed to play a particularly important role in regulatingimmune and inflammatory responses is the integrin family. This family ofcell surface glycoproteins has a typical non-covalently linkedheterodimer structure. At least 16 different integrin alpha chains and 8different integrin beta chains have been identified [Newman, P. et al,Molecular Medicine Today, 304, (1996)]. The members of the family aretypically named according to their heterodimer composition althoughtrivial nomenclature is widespread in the field. Thus the integrin α4β1consists of the integrin alpha 4 chain associated with the integrin beta1 chain, but is also widely referred to as Very Late Antigen 4 or VLA-4.Not all of the potential pairings of integrin alpha and beta chains haveyet been observed in nature and the integrin family has been subdividedinto a number of subgroups based on the pairings that have beenrecognised to date [Sonnenberg, A., Current Topics in Microbiology andImmunology, 184, 7, (1993)].

[0004] The importance of integrin function in normal physiologicalresponses is highlighted by two human deficiency diseases in whichintegrin function is defective. Thus in the disease termed LeukocyteAdhesion Deficiency (LAD) there is a defect in one of the families ofintegrins expressed on leukocytes [Marlin, S. D. et al, J. Exp. Med.164, 855, (1986)]. Patients suffering from this disease have a reducedability to recruit leukocytes to inflammatory sites and suffer recurrentinfections, which in extreme cases may be fatal. In the case of patientssuffering from the disease termed Glanzman's thrombasthenia (a defect ina member of the beta 3 integrin family) there is a defect in bloodclotting (Hodivala-Dilke, K. M., J. Clin. Invest. 103, 229, (1999)].

[0005] The potential to modify integrin function in such a way as tobeneficially modulate cell adhesion has been extensively investigated inanimal models using specific antibodies and peptides that block variousfunctions of these molecules [e.g. Issekutz, T. B., J. Immunol. 149,3394, (1992); Li, Z. et al, Am. J. Physiol. 263, L723, (1992); Mitjans,F. et al, J. Cell Sci. 108, 2825, (1995); Brooks, P. C. et al, J. Clin.Invest. 96, 1815, (1995); Binns, R. M. et al, J. Immunol. 157, 4094,(1996); Hammes, H. -P. et al, Nature Medicine 2, 529, (1996); Srivata,S. et al, Cardiovascular Res. 36, 408 (1997)]. A number of monoclonalantibodies which block integrin function are currently beinginvestigated for their therapeutic potential in human disease, and one,ReoPro, a chimeric antibody against the platelet integrin αIIbβ3 is inuse as a potent anti-thrombotic agent for use in patients withcardiovascular complications following coronary angioplasty.

[0006] Integrins recognize both cell surface and extracellular matrixligands, and ligand specificity is determined by the particularalpha-beta subunit combination of the molecule [Newman, P., ibid]. Oneparticular integrin subgroup of interest involves the α4 chain which canpair with two different beta chains β1 and β7 [Sonnenberg, A., ibid].The α4β1l pairing occurs on many circulating leukocytes (for examplelymphocytes, monocytes, eosinophils and basophils) although it is absentor only present at low levels on circulating neutrophils. α4β1 binds toan adhesion molecule (Vascular Cell Adhesion Molecule-1 also known asVCAM-1) frequently up-regulated on endothelial cells at sites ofinflammation [Osborne, L., Cell, 62, 3, (1990)]. The molecule has alsobeen shown to bind to at least three sites in the matrix moleculefibronectin [Humphries, M. J. et al, Ciba Foundation Symposium, 189,177, (1995)]. Based on data obtained with monoclonal antibodies inanimal models it is believed that the interaction between α4β1 andligands on other cells and the extracellular matrix plays an importantrole in leukocyte migration and activation [Yednock, T. A. et al,Nature, 356, 63, (1992); Podolsky, D. K. et al, J. Clin. Invest. 92,372, (1993); Abraham, W. M. et al, J. Clin. Invest. 93, 776, (1994)].

[0007] The integrin generated by the pairing of α4 and β7 has beentermed LPAM-1 [Holzmann, B. and Weissman, I. L., EMBO J. 8, 1735,(1989)]. The α4β7 pairing is expressed on certain sub-populations of Tand B lymphocytes and on eosinophils [Erle, D. J. et al, J. Immunol.153, 517 (1994)]. Like α4β1, α4β7 binds to VCAM-1 and fibronectin. Inaddition, α4β7 binds to an adhesion molecule believed to be involved inthe homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C.et al, Cell, 74, 185, (1993)]. The interaction between α4β7 and MAdCAM-1may also be important sites of inflammation outside of mucosal tissue[Yang, X. -D. et al, PNAS, 91, 12604, (1994)].

[0008] Regions of the peptide sequence recognizeded by α4β1 and α4β7when they bind to their ligands have been identified. α4β1 seems torecognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSPsequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst α4β7 recognisesa LDT sequence in MAdCAM-1 [Birskin, M. J. et al, J. Immunol. 156, 719,(1996)]. There have been several reports of inhibitors of theseinteractions being designed from modifications of these short peptidesequences [Cardarelli, P. M. et al, J. Biol. Chem., 269, 18668, (1994);Shorff, H. N. et al, Biorganic Med. Chem. Lett., 6, 2495, (1996);Vanderslice, P. et al, J. Immunol., 158, 1710, (1997)]. It has also beenreported that a short peptide sequence derived from the α4β1 bindingsite in fibronectin can inhibit a contact hypersensitivity reaction in atrinitrochlorobenzene sensitised mouse [Ferguson, T. A., et al, PNAS,88, 8072, (1991)].

[0009] Since the alpha 4 subgroup of integrins are predominantlyexpressed on leukocytes their inhibition can be expected to bebeneficial in a number of immune or inflammatory disease states.However, because of the ubiquitous distribution and wide range offunctions performed by other members of the integrin family it isimportant to be able to identify selective inhibitors of the alpha 4subgroup.

[0010] We have now found a group of 2,7-naphthyridines which are potentand selective inhibitors of α4-integrins. Members of the group are ableto inhibit α4 integrins such as α4β1 and α4β7 at concentrations at whichthey generally have no or minimal inhibitory action on a integrins ofother subgroups. The 2,7-naphthyridines also show unexpectedly highmetabolic stability when compared to other naphthyridines. The compoundsare thus of use in medicine, for example in the prophylaxis andtreatment of immune or inflammatory disorders as described hereinafter.

[0011] Thus according to one aspect of the invention we provide acompound of formula (1):

[0012] wherein

[0013] Ar¹ is an optionally substituted 2,7-naphthridin-1-yl group;

[0014] L² is a covalent bond or a linker atom or group;

[0015] Ar² is an optionally substituted aromatic or heteroaromaticchain;

[0016] Alk is a chain —CH₂CH(R)—, —CH═C(R)—,

[0017]  in which R is a carboxylic acid (—CO₂H) or a derivative orbiostere thereof;

[0018] R¹ is a hydrogen atom or a C₁₋₆alkyl group;

[0019] L¹ is a covalent bond or a linker atom or group;

[0020] Alk¹ is an optionally substituted aliphatic chain;

[0021] n is zero or the integer 1;

[0022] R² is a hydrogen atom or an optionally substitutedheteroaliphatic, cycloaliphatic, heterocycloaliphatic,polycycloalphatic, heteropolycyclo-aliphatic, aromatic or heteroaromaticgroup;

[0023] and the salts, solvates, hydrates and N-oxides thereof.

[0024] It will be appreciated that compounds of formula (1) may have oneor more chiral centers, and exist as enantiomers or diastereomers. Theinvention is to be understood to extend to all such enantiomers,diastereomers and mixtures thereof, including racemates. Formula (1) andthe formulae hereinafter are intended to represent all individualisomers and mixtures thereof, unless stated or shown otherwise.

[0025] The 2,7-naphthyridin-1-yl group represented by Ar¹ may beoptionally substituted on any available carbon atom. One, two, three ormore of the same or different substituents (R¹⁶) may be present and eachsubstituent may be selected for example from an atom or group-L³(Alk²)_(t)L⁴(R⁴)_(u) in which L³ and L⁴, which may be the same ordifferent, is each a covalent bond or a linker atom or group, t is zeroor the integer 1, u is an integer 1, 2 or 3, Alk² is an aliphatic orheteroaliphatic chain and R⁴ is a hydrogen or halogen atom or a groupselected from optionally substituted C₁₋₆alkyl or C₃₋₈ cycloalkyl, —OR⁵[where R⁵ is a hydrogen atom, an optionally substitued C₁₋₆alkyl or C₃₋₈cycloalkyl group], —SR⁵, —NR⁵R⁶ [where R⁶ is as just defined for R⁵ andmay be the same or different], —NO₂, —CN, —CO₂R⁵, —SO₃H, —SOR⁵, —SO₂R⁵,—SO₃R⁵, —OCO₂R⁵, —CONR⁵R⁶, —OCONR⁵R⁶, —CSNR⁵R⁶, —COR⁵, —OCOR⁵,—N(R⁵)COR⁶, —N(R⁵)CSR⁶, —SO₂N(R⁵)(R⁶), —N(R⁵)SO₂R⁶—N(R⁵)CON(R⁶)(R⁷)[where R⁷ is a hydrogen atom, an optionally substituted C₁₋₆alkyl orC₃₋₈cycloalkyl group], —N(R⁵)CSN(R⁶)(R⁷) or —N(R⁵)SO₂N(R⁶)(R⁷), providedthat when t is zero and each of L³ and L⁴ is a covalent bond then u isthe integer 1 and R⁴ is other than a hydrogen atom

[0026] When L³ and/or L⁴ is present in these substituents as a linkeratom or group it may be any divalent linking atom or group. Particularexamples include —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—,—S(O)—, —S(O)₂—, —N(R⁸)— [where R⁸ is a hydrogen atom or an optionallysubstituted C₁₋₆alkyl group], —N(R⁸)O—, —N(R⁸)N—, —CON(R⁸)—,—OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—,—S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)—, or—N(R⁸)SO₂N(R⁸)— groups. Where the linker group contains two R⁸substituents, these may be the same or different.

[0027] When R⁴, R⁵, R⁶, R⁷ and/or R⁸ is present as a C₁₋₆alkyl group itmay be a straight or branched C₁₋₆alkyl group, e.g. a C₁₋₃alkyl groupsuch as a methyl or ethyl group. C₃₋₈cycloalkyl groups represented byR⁴, R⁵, R⁶, R⁷ and/or R⁸ include C₃₋₆cycloalkyl groups e.g. cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituentswhich may be present on such groups include for example one, two orthree substituents which may be the same or different selected fromhalogen atoms, for example fluorine, chlorine, bromine or iodine atoms,or hydroxy or C₁₋₆alkoxy e.g. methoxy or ethoxy groups.

[0028] When the groups R⁵ and R⁶ or R⁶ and R⁷ are both C₁₋₆alkyl groupsthese groups may be joined, together with the N atom to which they areattached, to form a heterocyclic ring. Such heterocyclic rings may beoptionally interrupted by a further heteroatom selected from —O—, —S— or—N(R⁵)—. Particular examples of such heterocyclic rings includepiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyland piperazinyl rings.

[0029] When Alk² is present as an aliphatic or heteroaliphatic chain itmay be for example any divalent chain corresponding to thebelow-mentioned aliphatic chains described for Alk¹ or heteroaliphaticgroups described for R2 in which one of the terminal hydrogen atoms isreplaced by a bond.

[0030] Halogen atoms represented by R⁴ in the optional Ar¹ substituentsinclude fluorine, chlorine, bromine, or iodine atoms.

[0031] Examples of the substituents represented by-L³(Alk²)_(t)L⁴(R⁴)_(u) when present in Ar¹ groups in compounds of theinvention include atoms or groups -L³Alk²L⁴R⁴, -L³Alk²R⁴, -L³R⁴, -R4 and-Alk²R⁴ wherein L³, AlK², L⁴ and R⁴ are as defined above. Particularexamples of such substituents include -L³CH₂L⁴R⁴, -L³CH(CH₃)L⁴R⁴,-L³CH(CH₂)₂L⁴R⁴, L³CH₂R⁴, -L³CH(CH₃)R⁴, -L³(CH₂)₂R⁴, —CH₂R⁴, —CH(CH₃)R⁴, —(CH₂)₂R⁴ and —R⁴ groups.

[0032] Thus the 2,7-naphthyridin-1-yl group in compounds of theinvention may be optionally substituted for example by one, two, threeor more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms,and/or C₁₋₆alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl ort-butyl, C₃₋₈cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, C₁₋₆hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or—C(OH)(CF₃)₂, carboxyC₁₋₆alkyl, e.g. carboxyethyl, C₁₋₆alkylthio e.g.methylthio or ethylthio, carboxyC₁₋₆alkylthio, e.g. carboxymethylthio,2-carboxyethylthio or 3-carboxypropylthio, C₁₋₆alkoxy, e.g. methoxy orethoxy, hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, haloC₁₋₆alkyl, e.g.—CF₃, —CHF₂, CH₂F, haloC₁₋₆alkoxy, e.g. —OCF₃, —OCHF₂, —OCH₂F,C₁₋₆alkylamino, e.g. methylamino or ethylamino, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g.ethylaminoethyl, C₁₋₆ dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl,aminoC₁₋₆alkoxy, e.g. aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g.methylaminoethoxy, C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g.dimethylamino-ethoxy, diethylaminoethoxy, isopropylaminoethoxy, ordimethylamino-propoxy, nitro, cyano, amidino, hydroxyl (—OH), formyl[HC(O)—], carboxyl (—CO₂H), —CO₂Alk³ [where Alk³ is as defined below forAlk⁷], C₁₋₆ alkanoyl e.g. acetyl, thiol (—SH), thioC₁₋₆alkyl, e.g.thiomethyl or thioethyl, sulphonyl (—SO₃H), —SO₃Alk³,C₁₋₆alkylsulphinyl, e.g. methylsulphinyl, C₁₋₆alkylsulphonyl, e.g.methylsulphonyl, aminosulphonyl (—SO₂NH₂), C₁₋₆ alkylaminosulphonyl,e.g. methylaminosulphonyl or ethylaminosulphonyl,C₁₋₆dialkylaminosulphonyl, e.g. dimethylaminosulphonyl ordiethylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl,e.g. methylaminocarbonyl or ethylaminocarbonyl,C₁₋₆dialkylaminocarbonyl, e.g. dimethylaminocarbonyl ordiethylaminocarbonyl, aminoC₁₋₆alkylaminocarbonyl, e.g.aminoethylaminocarbonyl, C₁₋₆dialkylaminoC₁₋₆alkylaminocarbonyl, e.g.diethylaminoethylaminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethylamino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, C₁₋₆alkylsulphonylamino, e.g.methylsulphonylamino or ethylsulphonylamino, C₁₋₆dialkylsulphonylamino,e.g. dimethylsulphonylamino or diethylsulphonylamino,aminosulphonylamino (—NHSO₂NH₂), C₁₋₆alkylaminosulphonylamino, e.g.methylaminosulphonylamino or ethylaminosulphonylamino,C₁₋₆dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino ordiethylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylamino-C₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino groups.

[0033] L² when present as part of the group R¹ in compounds of theinvention may be a linker atom or group L^(2a) or a linker-Alk^(a)(L^(2a))_(v)-, where Alk^(a) is an optionally substitutedaliphatic or heteroaliphatic chain as previously defined for Alk²,L^(2a) is a covalent bond or a linker atom or group as described abovefor L³ and L⁴, and y is zero or the integer 1.

[0034] Optionally substituted aromatic or heteroaromatic groupsrepresented by Ar² include those aromatic or heteroaromatic groupsdescribed hereinafter in relation to R² aromatic or heteroaromaticgroups respectively. The optional substituents which may be present onthese groups include one, two, three or four optional substituents(R^(17a), R^(17b), R^(17c), and R^(17d)) where such substituents includethose R¹⁶ optional substituents as described hereinbefore.

[0035] It will be appreciated that when the optional substituentsR^(17a), R^(17b), R^(17c) and R^(17d) are absent then the aromatic orheteroaromatic ring Ar² is substituted by hydrogen atoms in place ofthose substituents.

[0036] When the group R is present in compounds of the invention as aderivative of a carboxylic acid it may be for example a carboxylic acidester or amide. Particular esters and amides include —CO₂Alk⁷ and—CONR⁵R⁶ groups as defined herein. When R is a biostere of a carboxylicacid it may be for example a tetrazole or other acid such as phosphonicacid, phosphinic acid, sulphonic acid, sulphinic acid or boronic acid oran acylsulphonamide group.

[0037] Esters (—CO₂Alk⁷) and amide (—CONR⁵R⁶) derivatives of thecarboxylic acid group (—CO₂H) in compounds of formula (1) mayadvantageously be used as prodrugs of the active compound. Such prodrugsare compounds which undergo biotransformation to the correspondingcarboxylic acid prior to exhibiting their pharmacological effects andthe invention particularly extends to produgs of the acids of formula(1). Such prodrugs are well known in the art, see for exampleInternational Patent Application No. WO00/23419, Bodor, N. (AlfredBenzon Symposium, 1982, 17, 156-177), Singh, G. et al (J. Sci. Ind.Res., 1996, 55, 497-510) and Bundgaard, H., (Design of Prodrugs, 1985,Elsevier, Amsterdam).

[0038] Esterified carboxyl groups represented by the group —CO₂Alk⁷wherein Alk⁷ include groups is a straight or branched optionallysubstituted C₁₋₈alkyl group such as a methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl or t-butyl group, an optionally substitutedC₂₋₈alkenyl group such as a propenyl e.g. 2-propenyl or butenyl e.g.2-butenyl or 3-butenyl group, an optionally substituted C₂₋₈alkynylgroup such as a ethynyl, propynyl e.g. 2-propynyl or butynyl e.g.2-butynyl or 3-butynyl group, an optionally substituted C₃₋₈cycloalkylgroup such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl group; an optionally substituted C₃₋₈cycloalkylC₁₋₈alkylgroup such as a cyclopentylmethyl, cyclohexylmethyl or cyclohexylethylgroup; an optionally substituted C₃₋₈heterocycloalkylC₁₋₆alkyl groupsuch as a morpholinyl-N-ethyl, thiomorpholinyl-N-methyl,pyrrolidinyl-N-ethyl, pyrrolidinyl-N-propyl, piperidinyl-N-ethyl,pyrazolidinyl-N-methyl or piperazinyl-N-ethyl group; an optionallysubstituted C₁₋₆alkyloxyC₁₋₆alkyl group such as a methyloxyethyl orpropyloxyethyl group; an optionally substituted C₁₋₆alkylthioC₁₋₆alkylgroup such as an ethylthioethyl group; an optionally substitutedC₁₋₆alkylsulfinylC₁₋₆alkyl group such as an methylsulfinylethyl group;an optionally substituted C₁₋₆alkylsulfonylC₁₋₆alkyl group such as anmethylsulfonylmethyl group; an optionally substitutedC₃₋₈cycloalkyloxyC₁₋₆alkyl group such as a cyclohexyloxy-methyl group;an optionally substituted C₃₋₈cycloalkylthioC₁₋₆alkyl group such as acyclopentylthiomethyl group; an optionally substitutedC₃₋₈cycloalkylsulfinylC₁₋₆alkyl group such as acyclopentylsulfinylmethyl group; an optionally substitutedC₃₋₈cycloalkylsulfonylC₁₋₆alkyl group such as acyclopentylsulfonylmethyl group; an optionally substitutedC₁₋₆alkyloxycarbonylC₁₋₆alkyl group such as isobutoxycarbonylpropylgroup; an optionally substituted C₁₋₆alkyloxycarbonylC₁₋₆alkenyl groupsuch as isobutoxycarbonylpentenyl group; an optionally substitutedC₁₋₆alkyloxycarbonyloxyC₁₋₆alkyl group such as anisopropoxycarbonyloxyethyl e.g. a 1-(isopropoxycarbonyloxy) ethyl,2-(isopropoxycarbonyloxy)ethyl or ethyloxycarbonyloxymethyl group; anoptionally substituted C₁₋₆alkyloxycarbonyloxyC₁₋₆alkenyl group such asa isopropoxycarbonyloxybutenyl group, an optionally substitutedC₃₋₈cycloalkyloxycarbonyloxyC₁₋₆alkyl group such as acyclohexyloxycarbonyloxyethyl, e.g. a 2-(cyclohexyloxycarbonyloxy)ethylgroup, an optionally substituted N-di-C₁₋₈alkylaminoC₁₋₈alkyl group suchas a N-dimethylaminoethyl or N-diethylaminoethyl group; an optionallysubstituted N—C₆₋₁₂aryl-N-C₁₋₆alkylaminoC₁₋₆alkyl group such as aN-phenyl-N-methylaminomethyl group; an optionally substitutedN-di-C₁₋₈alkylcarbamoylC₁₋₈alkyl group such as aN-diethylcarbamoylmethyl group; an optionally substitutedC₆₋₁₀arylC₁₋₆alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₀aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₀aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; a C₆₋₁₂arylthioC₁₋₈alkyl group such as anoptionally substituted phenylthioethyl group; aC₆₋₁₂arylsulfinylC₁₋₈alkyl group such as an optionally substitutedphenylsulfinylmethyl group; a C₆₋₁₂arylsulfonylC₁₂₋₈alkyl group such asan optionally substituted phenylsulfonylmethyl group; an optionallysubstituted C₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a acetoxymethyl,ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl orpropionyloxypropyl group; an optionally substituted C₄₋₈imidoC₁₋₈alkylgroup such as a succinimidomethyl or phthalamidoethyl group; aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxypropyl group or a triglyceride such as a2-substituted triglyceride e.g. a 1,3-di-C₁₋₈alkylglycerol-2-yl groupsuch as a 1,3-diheptylglycerol-2-yl group.

[0039] Optional substituents present on the Alk⁷ group include R^(13a)substituents described above.

[0040] It will be appreciated that in the forgoing list of Alk⁷ groupsthe point of attachment to the remainder of the compound of formula (1)is via the last described part of the Alk⁷ group. Thus, for example amethoxyethyl group would be attached by the ethyl group, whilst amorpholinyl-N-ethyl group would be attached via the N-ethyl group.

[0041] It will be further appreciated that in the forgoing list of Alk⁷groups, where not specifically mentioned, alkyl groups may be replacedby alkenyl or alkynyl groups where such groups are as definedhereinafter for Alk¹. Additionally these alkyl, alkenyl or alkynylgroups may optionally be interrupted by one, two or three linker atomsor groups where such linker atoms and groups are as previously definedfor L³.

[0042] When the group R² is present in compounds of the invention as aC₁₋₆alkyl group it may be for example a straight or branched C₁₋₆alkylgroup, e.g. a C₁₋₃alkyl group such as a methyl or ethyl group.

[0043] The linker atom or group represented by L¹ in compounds offormula (1) may be any linker atom or group as described above for thelinker atom or group L³.

[0044] When the group Alk¹ is present in compounds of formula (1) as anoptionally substituted aliphatic chain it may be an optionallysubstituted C₁₋₁₀ aliphatic chain. Particular examples includeoptionally substituted straight or branched chain C₁₋₆ alkylene, C₂₋₆alkenylene, or C₂₋₆ alkynylene chains.

[0045] Particular examples of aliphatic chains represented by Alk¹include optionally substituted —CH₂—, —(CH₂)₂—, —CH(CH₃)CH₂—,—(CH₂)₂CH₂—, —(CH₂)₃CH₂—, —CH(CH₃)(CH₂)₂—, —CH₂CH(CH₃)CH₂—,—C(CH₃)₂CH₂—, —CH₂C(CH₃)₂CH₂—, —(CH₂)₂C(CH₃)₂CH₂—, —(CH₂)₄CH₂—,—(CH₂)₅CH₂—, —CHCH—, —CHCHCH₂—, —CH₂CHCH—, —CHCHCH₂CH₂—, —CH₂CHCHCH₂—,—(CH₂)₂CHCH—, —CC—, —CCCH₂—, —CH₂CC—, —CCCH₂CH₂—, —CH₂CCCH₂— or—(CH₂)₂CCH— groups.

[0046] Heteroaliphatic groups represented by the group R² in thecompounds of formula (1) include the aliphatic chains just described forAlk¹ but with each containing a terminal hydrogen atom and additionallycontaining one, two, three or four heteroatoms or heteroatom-containinggroups. Particular heteroatoms or groups include atoms or groups L⁵where L⁵ is as defined above for L³ when L³ is a linker atom or group.Each L⁵ atom or group may interrupt the aliphatic group, or may bepositioned at its terminal carbon atom to connect the group to anadjoining atom or group. Particular examples include optionallysubstituted -L⁵CH₃, —CH₂L⁵CH₃, -L⁵CH₂CH₃, —CH₂L⁵CH₂CH₃, —(CH₂)₂L⁵CH₃,—(CH₂)₃L⁵CH₃, -L⁵(CH₂)₃, and —(CH₂)₂L⁵CH₂CH₃ groups.

[0047] The optional substituents which may be present on aliphatic orheteroaliphatic chains represented by Alk¹ and R² respectively includeone, two, three or more substituents where each substituent may be thesame or different and is selected from halogen atoms, e.g. fluorine,chlorine, bromine or iodine atoms, or —OH, —CO₂H, —CO₂R⁹, where R⁹ is anoptionally substituted straight or branched C₁₋₆alkyl group as definedabove for R⁴, —CONHR⁹, —CON(R⁹)₂, —COCH₃, C₁₋₆alkoxy, e.g. methoxy orethoxy, thiol, —S(O)R⁹, —S(O)₂R⁹, C₁₋₆alkylthio e.g. methylthio orethylthio, amino or substituted amino groups. Substituted amino groupsinclude —NHR⁹ and —N(R⁹)₂ groups . Where two R⁹ groups are present inany of the above substituents these may be the same or different.

[0048] Optionally substituted cycloaliphatic groups represented by thegroup R² in compounds of the invention include optionally substitutedC₃₋₁₀ cycloaliphatic groups. Particular examples include optionallysubstituted C₃₋₁₀ cycloalkyl, e.g. C₃₋₇ cycloalkyl or C₃₋₁₀cycloalkenyl, e.g. C₃₋₇ cycloalkenyl groups.

[0049] Optionally substituted heterocycloaliphatic groups represented bythe group R² include optionally substituted C₃₋₁₀heterocycloaliphaticgroups. Particular examples include optionally substitutedC₃₋₁₀heterocycloalkyl, e.g. C₃₋₇ heterocycloalkyl, orC₃₋₁₀heterocycloalkenyl, e.g. C₃₋₇ hetercycloalkenyl groups, each ofsaid groups containing one, two, three or four heteroatoms orheteroatom-containing groups L⁵ as defined above.

[0050] Optionally substituted polycycloaliphatic groups represented bythe group R² include optionally substitued C₇₋₁₀ bi- or tricycloalkyl orC₇₋₁₀bi- or tricycloalkenyl groups. Optionally substitutedheteropolycycloaliphatic groups represented by the group R² include theoptionally substituted polycycloalkyl groups just described, but witheach group additionally containing one, two, three or four L⁵ atoms orgroups.

[0051] Particular examples of cycloaliphatic, polycycloaliphatic,heterocycloaliphatic and heterpolyocycloaliphatic groups represented bythe group R² include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl,2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl,norbornenyl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl,pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl,e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl,pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or4-pyranyl, piperidinyl, homopiperidinyl (azepanyl),heptamethyleneiminyl, piperidinone, 1,4-dioxanyl, morpholinyl,morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl,homopiperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl,or 1,3,5,-oxadiazinyl groups.

[0052] The optional substituents which may be present on thecycloaliphatic, polycycloaliphatic, heterocycloaliphatic orpolyheterocycloaliphatic groups represented by the group R² include one,two, three or more substituents each selected from halogen atoms, e.g.fluorine, chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methylor ethyl, haloC₁₋₆alkyl, e.g. halomethyl or haloethyl such asdifluoromethyl or trifluoromethyl, optionally substituted by hydroxyl,e.g. —C(OH)(CF₃)₂, C₁₋₆alkoxy, e.g. methoxy or ethoxy, haloC₁₋₆alkoxy,e.g. halomethoxy or haloethoxy such as difluoromethoxy ortrifluoromethoxy, thiol, C₁₋₆alkylthio e.g. methylthio or ethylthio, or-(Alk⁴)_(v)R¹⁰ groups in which Alk⁴ is a straight or branchedC₁₋₃alkylene chain, v is zero or an integer 1 and R¹⁰ is a —OH, —SH,—N(R¹¹)₂, (in which R¹¹ is an atom or group as defined herein forR⁸)—CN, —CO₂R¹¹, —NO₂, —CON(R¹¹)₂, —CSN(R¹¹)₂, —COR¹¹, —CSN(R¹¹)₂,—N(R¹¹)COR¹¹, —N(R¹¹)CSR¹¹,—SO₂N(R¹¹)₂, —N(R¹¹)SO₂R¹¹, —N(R¹¹)CON(R¹¹)₂,—N(R¹¹)CSN(R¹¹), N(R¹¹)SO₂N(R¹¹)₂ or optionally substituted phenylgroup. Where two R¹¹ atoms or groups are present in these substituentsthese may be the same or different. Optionally substituted phenyl groupsinclude phenyl substituted by one, two or three of the R¹³ groupsdescribed below.

[0053] Particular examples of Alk⁴ chains include —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH(CH₃)CH₂— chains.

[0054] Additionally, when the group R² is a heterocycloaliphatic groupcontaining one or more nitrogen atoms each nitrogen atom may beoptionally substituted by a group -(L⁶)_(p)(Alk⁵)_(q)R¹² in which L⁶ is—C(O)—, —C(O)O—, —C(S)—, —S(O)₂—, —CON(R¹¹)—, —CSN(R¹¹)— or SO₂N(R¹¹)—;p is zero or an integer 1; Alk⁵ is an optionally substituted aliphaticor heteroaliphatic chain; q is zero or an integer 1; and R¹² is ahydrogen atom or an optionally substituted cycloaliphatic,heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic,aromatic or heteroaromatic group.

[0055] Optionally substituted aliphatic or heteroaliphatic chainsrepresented by Alk⁵ include those optionally substituted chainsdescribed above for Alk².

[0056] Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic orpolyheterocyclo-aliphatic groups represented by R¹² include those groupsjust described for the group R². Optional substituents which may bepresent on these groups include those described above in relation toAlk¹ and R² aliphatic and heteroaliphatic chains.

[0057] Optionally substituted aromatic groups represented by R² whenpresent in the group R¹ include for example optionally substitutedmonocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl,1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.

[0058] Optionally substituted heteroaromatic groups represented by thegroup R² include for example optionally substituted C₁₉ heteroaromaticgroups containing for example one, two, three or four heteroatomsselected from oxygen, sulphur or nitrogen atoms. In general, theheteroaromatic groups may be for example monocyclic or bicyclic fusedring heteroaromatic groups. Monocyclic heteroaromatic groups include forexample five- or six-membered heteroaromatic groups containing one, two,three or four heteroatoms selected from oxygen, sulphur or nitrogenatoms. Bicyclic heteroaromatic groups include for example eight- tothirteen-membered fused-ring heteroaromatic groups containing one, twoor more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

[0059] Particular examples of heteroaromatic groups of these typesinclude pyrrolyl, furyl, thienyl, imidazolyl, N-C₁₋₆alkylimidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,[2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl,isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl,pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl,tetrazolyl, 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl,phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.

[0060] Optional substituents which may be present on the aromatic orheteroaromatic groups represented by the group R² include one, two,three or more substituents, each selected from an atom or group R¹³ inwhich R¹³ is —R^(13a) or -Alk⁶(R^(13a))m, where R^(13a) is a halogenatom, or an amino (—NH₂), substituted amino, nitro, cyano, amidino,hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO₂H),esterified carboxyl, thiol (—SH), substituted thiol, —COR¹⁴ [where R¹⁴is an -Alk⁶(R^(13a))_(m), cycloaliphatic, heterocycloaliphatic, aryl orheteroaryl group], —CSR¹⁴, —SO₃H, —SOR¹⁴, —SO₂R¹⁴, —SO₃R¹⁴, —SO₂NH₂,—SO₂NHR¹⁴, —SO₂N(R¹⁴)₂, —CONH₂, —CSNH₂, —CONHR¹⁴, —CSNHR¹⁴, —CON[R¹⁴]₂,—CSN(R¹⁴)₂, —N(R¹¹)SO₂R¹⁴, —N(SO₂ R¹⁴)₂, —NH(R¹¹)SO₂NH₂,—N(R¹¹)SO₂NHR¹⁴, —N(R¹¹)SO₂N(R¹⁴)₂, —N(R¹¹)COR¹⁴, —N(R¹¹)CONH₂,—N(R¹¹)CONHR¹⁴, —N(R¹¹)CON(R¹⁴)₂, —N(R¹¹)CSNH₂, —N(R¹¹)CSNHR¹⁴,—N(R¹¹)CSN(R¹⁴)₂, —N(R¹¹)CSR¹⁴, —N(R¹¹)C(O)OR¹⁴, —SO₂NHet¹ [where —NHet¹is an optionally substituted C₅₋₇cyclicamino group optionally containingone or more other —O— or —S— atoms or —N(R¹¹)—, —C(O)—, —C(S)—, S(O) or—S(O)₂ groups], —CONHet¹, —CSNHet¹, —N(R¹¹)SO₂NHet¹, —N(R¹¹)CONHet¹,—N(R¹¹)CSNHet¹, —SO₂N(R¹¹)Het² [where Het² is an optionally substitutedmonocyclic C₅₋₇carbocyclic group optionally containing one or more —O—or —S— atoms or —N(R¹¹)—, —C(O)— or —C(S)— groups], —Het²,—CON(R¹¹)Het², —CSN(R¹¹)Het², —N(R¹¹)CON(R¹¹)Het², —N(R¹¹)CSN(R¹¹)Het²,cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group; Alk⁶ isa straight or branched C₁₋₆alkylene, C₂₋₆alkenylene or C₂₋₆alkynylenechain, optionally interrupted by one, two or three —O— or —S— atoms or—S(O)_(n) [where n is an integer 1 or 2] or —N(R¹⁵)— groups [where R¹⁵is a hydrogen atom or C₁₋₆alkyl, e.g. methyl or ethyl group]; and m iszero or an integer 1, 2 or 3. It will be appreciated that when two R¹¹or R¹⁴ groups are present in one of the above substituents, the R¹¹ orR¹⁴ groups may be the same or different.

[0061] When in the group -Alk⁶(R^(13a))_(m) m is an integer 1, 2 or 3,it is to be understood that the substituent or substituents R^(13a) maybe present on any suitable carbon atom in -Alk⁶. Where more than oneR^(13a) substituent is present these may be the same or different andmay be present on the same or different atom in -Alk⁶. Clearly, when mis zero and no substituent R^(13a) is present the alkylene, alkenyleneor alkynylene chain represented by Alk⁶ becomes an alkyl, alkenyl oralkynyl group.

[0062] When R^(13a) is a substituted amino group it may be for example agroup —NHR¹⁴ [where R¹⁴ is as defined above] or a group —N(R¹⁴)₂ whereineach R¹⁴ group is the same or different.

[0063] When R^(13a) is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

[0064] When R^(13a) is a substituted hydroxyl or substituted thiol groupit may be for example a group —OR¹⁴ or a —SR¹⁴ or —SC(═NH)NH₂ grouprespectively.

[0065] Esterified carboxyl groups represented by the group R^(13a)include groups of formula —CO₂Alk⁷ wherein Alk⁷ is a group as definedhereinbefore.

[0066] Esterified carboxyl groups represented by the group R^(13a)include groups of formula —CO₂Alk⁷ wherein Alk⁷ is a group as definedhereinbefore.

[0067] When Alk⁶ is present in or as a substituent it may be for examplea methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene,s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O)₂— or —N(R⁹)— groups.

[0068] Cycloaliphatic or heterocycloaliphatic groups represented by thegroups R^(13a) or R¹⁴ include those optionally substitutedC₃₋₁₀cycloaliphatic or C₃₋₁₀ heterocycloaliphatic groups described abovefor R².

[0069] Aryl or heteroaryl groups represented by the groups R^(13a) orR¹⁴ include mono- or bicyclic optionally substituted C₆₋₁₂ aromatic orC₁₋₉ heteroaromatic groups as described above for the group R². Thearomatic and heteroaromatic groups may be attached to the remainder ofthe compound of formula (1) by any carbon or hetero e.g. nitrogen atomas appropriate.

[0070] When —NHet¹ or —Het² forms part of a substituent R¹³ each may befor example an optionally substituted pyrrolidinyl, pyrazolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinylgroup. Additionally Het² may represent for example, an optionallysubstituted cyclopentyl or cyclohexyl group. Optional substituents whichmay be present on —NHet¹ or —Het² include those R⁷ substituentsdescribed above.

[0071] Particularly useful atoms or groups represented by R¹³ includefluorine, chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl,ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substitutedphenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl,morpholinyl, thiomorpholinyl, piperazinyl, e.g.t-butyloxycarbonylpiperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl,oxazolidinyl, thiazolidinyl, imidazolidinyl or piperidinyl,C₁₋₆hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC₁₋₆alkyl,e.g. carboxyethyl, C₁₋₆alkylthio e.g. methylthio or ethylthio,carboxyC₁₋₆alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or3-carboxypropylthio, C₁₋₆alkoxy, e.g. methoxy or ethoxy,hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy,pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C₄₋₇cycloalkyl, e.g.cyclobutyl, cyclopentyl, C₅₋₇cycloalkoxy, e.g. cyclopentyloxy,haloC₁₋₆alkyl, e.g. trifluoromethyl, haloC₁₋₆alkoxy, e.g.trifluoromethoxy, C₁₋₆alkylamino, e.g. methylamino, ethylamino orpropylamino, C6-12arylC1-6alkylamino, e.g. benzylamino,4-fluorobenzylamino or 4-hydroxyphenylethylamino, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, aminoC1-6alkylamino, e.g. aminoethylaminoor aminopropylamino, optionally substituted Het¹NC₁₋₆alkylamino, e.g.3-morpholinopropylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g. ethylaminoethyl,C₁₋₆dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl, aminoC₁₋₆alkoxy, e.g.aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g. methylaminoethoxy,C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g. dimethylaminoethoxy,diethylaminoethoxy, diisopropylaminethoxy, or dimethylaminopropoxy,hydroxyC₁₋₆alkylamino, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino or3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g.1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (—OH), formyl[HC(O)—], carboxyl (—CO₂H), —CO₂Alk⁷ [where Alk⁷ is as defined above],C₁₋₆alkanoyl e.g. acetyl, propyryl or butyryl, optionally substitutedbenzoyl, thiol (—SH), thioC₁₋₆alkyl, e.g. thiomethyl or thioethyl,—SC(═NH)NH₂, sulphonyl (—SO₃H), —SO₃Alk⁷, C₁₋₆alkylsulphinyl, e.g.methylsulphinyl, ethylsulphinyl or propylsulphinyl, C₁₋₆alkylsulphonyl,e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl(—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g. methylaminosulphonyl,ethylaminosulphonyl or propylaminosulphonyl C₁₋₆dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g.methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl,C₁₋₆dialkylaminocarbonyl, e.g. dimethylaminocarbonyl ordiethylaminocarbonyl, aminoC₁₋₆alkylaminocarbonyl, e.g.aminoethylaminocarbonyl, C₁₋₆alkylaminoC₁₋₆alkylaminocarbonyl, e.g.methylaminoethylaminocarbonyl, C₁₋₆dialkyl-aminoC₁₋₆alkylaminocarbonyl,e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethyl-amino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, —CONHC(═NH)NH₂,C₁₋₆alkyl-sulphonylamino, e.g. methylsulphonylamino orethylsulphonylamino, haloC₁₋₆alkylsulphonylamino, e.g.trifluoromethylsulphonylamino, C₁₋₆ dialkylsulphonylamino, e.g.dimethylsulphonylamino or diethylsulphonylamino, optionally substitutedphenylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂),C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g.dimethylaminosulphonylamino or diethylaminosulphonylamino, optionallysubstituted morpholinesulphonylamino ormorpholinesulphonylC₁₋₆alkylamino, optionally substitutedphenylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylaminoC₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino or optionally substituted benzyloxy,pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino,benzyloxycarbonylaminoC₁₋₆alkyl e.g. benzyloxycarbonylaminoethyl,thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.

[0072] Where desired, two R¹³ substituents may be linked together toform a cyclic group such as a cyclic ether, e.g. a C₁₋₆alkylenedioxygroup such as methylenedioxy or ethylenedioxy.

[0073] It will be appreciated that where two or more R¹³ substituentsare present, these need not necessarily be the same atoms and/or groups.In general, the substituent(s) may be present at any available ringposition in the aromatic or heteroaromatic group represented by R².

[0074] The presence of certain substituents in the compounds of formula(1) may enable salts of the compounds to be formed. Suitable saltsinclude pharmaceutically acceptable salts, for example acid additionsalts derived from inorganic or organic acids, and salts derived frominorganic and organic bases.

[0075] Acid addition salts include hydrochlorides, hydrobromides,hydroiodides, alkylsulphonates, e.g. methanesulphonates,ethanesulphonates, or isothionates, arylsulphonates, e.g.p-toluenesulphonates, besylates or napsylates, phosphates, sulphates,hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates,maleates, fumarates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

[0076] Salts derived from inorganic or organic bases include alkalimetal salts such as sodium or potassium salts, alkaline earth metalsalts such as magnesium or calcium salts, and organic amine salts suchas morpholine, piperidine, dimethylamine or diethylamine salts.

[0077] Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts.

[0078] The group Ar² in compounds of formula (1) is preferably anoptionally substituted phenylene group.

[0079] A particularly useful group of compounds according to theinvention has the formula (2):

[0080] wherein R¹⁶ is a hydrogen atom or an atom or group-L³(Alk²)_(t)L⁴(R⁴)_(u) in which L³, Alk², t, L⁴, R⁴, and u are aspreviously generally and particularly defined;

[0081] R^(17a) and R^(17b) bis each a hydrogen atom or an optionalsubstituent as defined for formula (1);

[0082] L¹, L², Ar2, Alk, R¹, Alk¹, n and R² are as defined for formula(1);

[0083] g is zero or the integer 1, 2, 3,4 or 5;

[0084] and the salts, solvates, hydrates and N-oxides thereof.

[0085] Particularly useful R¹⁶ substituents when present in compounds offormula (2) include halogen atoms, especially fluorine or chlorineatoms, or straight or branched C₁₋₆alkyl especially methyl, ethyl,propyl or isopropyl, C₁₋₃cycloalkyl especially cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, haloC₁₋₆alkyl especially halomethyl, mostespecially —CF₃ or —CHF₂ C₁₋₆alkoxy especially methoxy or ethoxy,haloC₁₋₆alkoxy especially halomethoxy, most especially —OCF₃, or —OCHF₂,—SR⁵ especially methylthio or ethylthio, —CN, —CO₂Alk³, especially—CO₂CH₃, —NO₂, amino (—NH₂), substituted amino (—NR⁵R⁶), and—N(R⁵)COCH₃, especially —NHCOCH₃ and —COR⁵, especially —COCH₃ groups.

[0086] Particularly useful R^(17a) and R^(17b) substituents when presentin compounds of formula (2) include those particularly usefulsubstituents as just described for R¹⁶.

[0087] In one preferred class of compounds of formula (2) g is zero.

[0088] In another preferred class of compounds of formula (2) g is theinteger 1 or 2.

[0089] Alk in compounds of the invention is preferably:

[0090] or, especially, —CH₂CH(R)—.

[0091] In one preferred class of compounds of formulae (1) and (2) R isa —CO₂H group.

[0092] In another preferred class of compounds of formulae (1) and (2) Ris an esterified carboxyl group of formula —CO₂Alk⁷. In this class ofcompound Alk⁷ is preferably a C₁₋₈alkyl group, especially a methyl,ethyl, propyl, i-propyl, butyl or pentyl group, an optionallysubstituted C₃₋₈cycloalkyl group, especially a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl group, an optionally substitutedC₆₋₁₀aryl group, especially a phenyl group, an optionally substitutedC₆₋₁₀arylC₁₋₆alkyl group, especially a benzyl group, an optionallysubstituted C₃₋₈heterocycloalkylC₁₋₆alkyl group, especially amorpholinyl-N-ethyl group, an optionally substitutedN-di-C₁₋₈alkylaminoC₁₋₈alkyl group, especially a N-dimethylaminoethyl orN-diethylaminoethyl group or a C₁₋₆alkyloxyC₁₋₆alkyl group, especially amethyloxyethyl group. Especially preferred esterified carboxyl groupsinclude —CO2CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃ and —CO₂CH(CH₃)₂ groups.

[0093] In general in compounds of formulae (1) and (2) R¹ is preferablya hydrogen atom.

[0094] In general in compounds of formulae (1) and (2) L² is preferablyL^(2a) where L^(2a) is an —O— atom or —N(R⁸)— group in which R⁸ ispreferably a hydrogen atom or a methyl group. An especially useful—N(R⁸)— group is —NH—.

[0095] In general in compounds of formulae (1) and (2) when n is zero orthe integer 1 the group R² may especially be an optionally substitutedheteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic orheteroaromatic group as defined herein. Particularly useful groups ofthis type include optionally substituted C₂₋₆heteroalkyl, particularlyC₁₋₃alkoxyC₁₋₃alkyl, especially methoxypropyl, optionally substitutedC₃₋₇cycloalkyl, especially optionally substituted cyclopropyl,cyclobutyl cyclopropyl or cyclohexyl, optionally substitutedC₅₋₇heterocycloaliphatic, especially optionally substitutedpyrrolidinyl, morpholinyl, thiomorpholinyl, or thiazolidinyl, especiallyoptionally substituted phenyl and optionally substitutedC₅₋₇heteroaromatic, especially optionally substituted pyridyl groups.Optional substituents on these groups include in particular R¹³ atoms orgroups where the group is an aromatic or heteroaromatic group and-(L⁶)_(p)(Alk⁵)_(q)R¹² groups as described earlier where the group is anitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl orthiazolidinyl, piperidinyl, homopiperidinyl, heptamethyleneiminyl,piperazinyl, homopiperazinyl, morpholinyl or thiomorpholinylpiperidinyl, homopiperidinyl, heptamethyleneiminyl, piperazinyl,morpholinyl or thiomorpholinyl group. Particularly useful-(L⁶)_(p)(Alk⁵)_(q)R¹² groups include those in which L⁶ is a —CO— group.Alk⁵ in these groups is preferably present (i.e. q is preferably aninteger 1) and in particular is a —CH₂— chain. Compounds of this type inwhich R¹² is a hydrogen atom or an optionally substituted aromatic orheteroaromatic group, especially an optionally substituted phenyl,pyridyl or imidazolyl group are particularly preferred.

[0096] In one preferred class of compounds of formulae (1) and (2) L¹ ispresent as a —N(R⁸)— group. Particularly useful —N(R⁸)— groups include—NH— and —N(C₁₋₆alkyl)—, especially —N(CH₃)—, —N(CH₂CH₃)— and—N(CH₂CH₂CH₃)— groups. In this class of compounds n is preferably theinteger 1 and Alk¹ is preferably an optionally substituted straight orbranched C₁₋₆alkylene chain. Particularly useful Alk¹ chains include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂— and —C(CH₃)₂CH₂—. R² in thisclass of compounds is preferably a hydrogen atom.

[0097] In another preferred class of compounds of formulae (1) and (2)L¹ is a covalent bond, n is the integer (1) and Alk¹ is an optionallysubstituted straight or branched C₁₋₆alkylene chain. Particularly usefulAlk¹ chains include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂— andespecially —C(CH₃)₂CH₂— chains. R² in this class of compounds ispreferably a hydrogen atom. A most especially useful optionallysubstituted Alk¹R² group is —C(CH₃)₃.

[0098] In another preferred class of compounds of formulae (1) and (2),La is a covalent bond, n is zero and R² is an optionally substitutedC₅₋₇heterocycloaliphatic group most especially an optionally substitutedC₅₋₇heterocycloalkyl group. Especially useful C₅₋₇heterocycloalkylgroups include optionally substituted piperidinyl, homopiperidinyl(azepanyl), heptamethyleneiminyl, pyrrolidinyl, piperazinyl,homopiperazinyl, morpholinyl and thiomorpholinyl groups. Most preferredC₅₋₇heterocycloaliphatic groups are those linked via a ring nitrogenatom to the remainder of the compound of formulae (1) or (2). Mostespecially useful C₅₋₇heterocycloaliphatic groups include optionallysubstituted pyrolidin-1-yl, piperidin-1-yl and homopiperidin-1-yl(azepan-1-yl) groups. Especially useful optional substituents on theseC₅₋₇heterocycloaliphatic groups include optionally substituted C₁₋₆alkylgroups, especially methyl, ethyl or i-propyl groups. Most preferredoptionally substituted C₅₋₇heterocycloaliphatic groups include2-methylpyrrolidin-1-yl, cis and trans 2,5-dimethylpyrrolidin-1-yl,2-methylpiperidin-yl and 2,6-dimethylpiperidin-1-yl, homopiperidin-1-yl(azepan-1-yl), 2-methylhomopiperidin-1-yl (2-methyazepan-1-yl) and cisand trans 2,7-dimethylhomopiperidin-1-yl groups.

[0099] Particularly useful compounds of the invention include:

[0100](S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0101] (S)-3[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0102](S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0103] (S )-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0104](S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0105](S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamino)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0106] (S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-( cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;

[0107] (S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[(2-[(2S),(5S)-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoicacid;

[0108](S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0109](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;

[0110](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;

[0111] (S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylaminolpropanoicacid;

[0112](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0113](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0114] (S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0115](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(trans-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionicacid;

[0116](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0117](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoic acid;

[0118](S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoicacid;

[0119](S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoicacid; and the salts, solvates, hydrates, N-oxides and carboxylic acidester, particularly methyl, ethyl, propyl and i-propyl esters thereof

[0120] Most especially preferred compounds of the invention include:

[0121](S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;

[0122] (S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid;

[0123](S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0124](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;

[0125](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0126](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-NN-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid, dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0127](S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;

[0128](S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoicacid;

[0129](S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoicacid;

[0130] and the salts, solvates, hydrates, N-oxides and carboxylic acidester, particularly methyl, ethyl, propyl and i-propyl esters thereof.

[0131] Compounds according to the inventions are potent and selectiveinhibitors of α4 integrins and have advantageous clearance properties,especially those compounds where R is a carboxylic ester or amide. Theability of the compounds to act in this way may be simply determined byemploying tests such as those described in the Examples hereinafter.

[0132] The compounds are of use in modulating cell adhesion and inparticular are of use in the prophylaxis and treatment of diseases ordisorders involving inflammation in which the extravasation ofleukocytes plays a role and the invention extends to such a use and tothe use of the compounds for the manufacture of a medicament fortreating such diseases or disorders.

[0133] Diseases or disorders of this type include inflammatory arthritissuch as rheumatoid arthritis vasculitis or polydermatomyositis, multiplesclerosis, allograft rejection, diabetes, inflammatory dermatoses suchas psoriasis or dermatitis, asthma and inflammatory bowel disease.

[0134] For the prophylaxis or treatment of disease the compoundsaccording to the invention may be administered as pharmaceuticalcompositions, and according to a further aspect of the invention weprovide a pharmaceutical composition which comprises a compound offormula (1) together with one or more pharmaceutically acceptablecarriers, excipients or diluents.

[0135] Pharmaceutical compositions according to the invention may take aform suitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

[0136] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, coloring andsweetening agents as appropriate.

[0137] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0138] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0139] The compounds for formula (1) may be formulated for parenteraladministration by injection e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoule or multi dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. For particle mediated administration the compounds offormula (1) may be coated on particles such as microscopic goldparticles.

[0140] In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection.

[0141] For nasal administration or administration by inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of an aerosol spray presentation for pressurisedpacks or a nebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

[0142] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack or dispensing device may beaccompanied by instructions for administration.

[0143] The quantity of a compound of the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccaladministration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

[0144] The compounds of the invention may be prepared by a number ofprocesses as generally described below and more specifically in theExamples hereinafter. In the following process description, the symbolsAr¹, Ar², Alk, R¹, R², L¹, L², Alk¹ and n when used in the formulaedepicted are to be understood to represent those groups described abovein relation to formula (1) unless otherwise indicated. In the reactionsdescribed below, it may be necessary to protect reactive functionalgroups, for example hydroxy, amino, thio or carboxy groups, where theseare desired in the final product, to avoid their unwanted participationin the reactions. Conventional protecting groups may be used inaccordance with standard practice [see, for example, Green, T. W. in“Protective Groups in Organic Synthesis”, John Wiley and Sons, 1999]. Insome instances, deprotection may be the final step in the synthesis of acompound of formula (1) and the processes according to the inventiondescribed hereinafter are to be understood to extend to such removal ofprotecting groups. For convenience the processes described below allrefer to a preparation of a compound of formula (1) but clearly thedescription applies equally to the preparation of compounds of formula(2).

[0145] Thus according to a further aspect of the invention, a compoundof formula (1) in which R is a —CO₂H group may be obtained by hydrolysisof an ester of formula (3):

[0146] where Alk represents a group

—CH₂CH(CO₂R^(y))—, —CH═CH(CO₂R^(y))—,

[0147] [where R^(y) is an alkyl group for example a C₁₋₆alkyl group]

[0148] The hydrolysis may be performed using either an acid or a basedepending on the nature of R^(y), for example an organic acid such astrifluoroacetic acid or an inorganic base such as lithium, sodium orpotassium hydroxide optionally in an aqueous organic solvent such as anamide e.g. a substituted amide such as dimethylformamide, an ether e.g.a cyclic ether such as tetrahydrofuran or dioxane or an alcohol e.g.methanol at a temperature from ambient to the reflux temperature. Wheredesired, mixtures of such solvents may be used.

[0149] According to a further aspect of the invention a compound offormula (1) may be prepared by displacement of a leaving group from acompound of formula (4):

[0150] where R^(a) is a leaving group, with an amine Ar¹L²Ar²AlkN(R¹)Hor a salt thereof. Suitable leaving groups represented by R^(a) includehalogen atoms, especially chlorine and bromine atoms, or alkoxy, e.g.methoxy, ethoxy or isopropoxy, aryloxy, e.g. dinitrophenyloxy, oraralkoxy, e.g. benzyloxy, groups.

[0151] The reaction may be performed in an inert solvent or mixture ofsolvents, for example a substituted amide such as dimethylformamide, analcohol such as ethanol and/or a halogenated hydrocarbon such asdichloromethane, at a temperature from 0° C. to the reflux temperature.Where necessary, for example when a salt of an amine Ar¹L²Ar²AlkN(R¹)His used, an organic base such as diisopropylethylamine can be added.

[0152] Any carboxylic acid group present in the intermediate of formula(4) or the amine Ar¹L²Ar²AlkN(R¹)H may need to be protected during thedisplacement reaction, for example as an ethyl ester. The desired acidmay then be obtained through subsequent hydrolysis, for example asparticularly described above and generally described below.

[0153] It will be appreciated that the displacement reaction may also beperformed on a compound of formula (5):

[0154] where R^(b) is a leaving group as defined for R^(a) using anintermediate R²(Alk¹)_(n)L¹H where -L¹H is a functional group such as anamine (—NH₂) using the reaction conditions just described.

[0155] Where desired the displacement reaction may also be performed onan intermediate of formulae (4) or (5), Ar¹L²Ar²AlkN(R¹)H orR²(Alk¹)_(n)L¹H which is linked, for example via its Ar¹ or R² group, toa solid support, such as a polystyrene resin. After the reaction thedesired compound of formula (1) may be displaced from the support by anyconvenient method, depending on the original linkage chosen.

[0156] Intermediates of formulae (4) and (5) are either readilyavailable or may be prepared from an intermediate of formula (6):

[0157] where R^(a) and R^(b) are as previously defined and an amineAr¹L²Ar²AlkN(R¹)H or R²(Alk¹)_(n)N(R⁸)H by displacement as justdescribed for the preparation of compounds of formula (1).

[0158] Intermediates of formulae Ar¹L²Ar²AlkN(R¹)H andR²(Alk¹)_(n)N(R⁸)H may be obtained from simpler, known compounds by oneor more standard synthetic methods employing substitution, oxidation,reduction or cleavage reactions. Particular substitution approachesinclude conventional alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulphonylation, nitration, formylation andcoupling procedures. It will be appreciated that these methods may alsobe used to obtain or modify other compounds of formulae (1) and (2)where appropriate functional groups exist in these compounds.

[0159] Thus compounds of the invention and intermediates thereto may beprepared by alkylation, arylation or heteroarylation. For example,compounds containing a -L¹H or -L²H group (where L¹ and L² is each alinker atom or group) may be treated with a coupling agentR²(Alk¹)_(n)X¹ or Ar¹X¹ respectively in which X¹ is a leaving atom orgroup such as a halogen atom, e.g. a fluorine, bromine, iodine orchlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g.trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g.p-toluenesulphonyloxy group.

[0160] The reaction may be carried out in the presence of a base such asa carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g.potassium t-butoxide, or a hydride, e.g. sodium hydride, or an organicamine e.g. triethylamine or N,N-diisopropylethylamine or a cyclic amine,such as N-methylmorpholine or pyridine, in a dipolar aprotic solventsuch as an amide, e.g. a substituted amide such as dimethylformamide oran ether, e.g. a cyclic ether such as tetrahydrofuran.

[0161] Intermediates of formulae Ar¹X¹ and R²(Alk¹)_(n)X¹ are generallyknown readily available compounds or may be prepared from knowncompounds by standard substitution and other synthetic procedures, forexample as described herein. Thus for example compounds of formula Ar¹X¹in which Ar¹ represents an optionally substituted 2,7-naphthyridin-1-ylgroup may be prepared from alcohols of formula Ar¹OH by reaction with ahalogenating agent, for example a phosphorous oxyhalide such asphosphorous oxychloride at an elevated temperature e.g. 110° C.

[0162] Intermediate alcohols of formula Ar¹OH in which Ar¹ represents anoptionally substituted 2,7-naphthyridin-1-yl group may be prepared bymethods well known to a person skilled in the art, e.g. by the method ofSakamoto, T. et al [Chem. Pharm. Bull. 33, 626-633, (1985)] or Baldwin,J, J. et al [J. Org. Chem, 43, 4878-4880, (1978)]. Thus for example themethod of Baldwin may be modified to allow the synthesis of intermediate3-substituted 2,7-naphthyridin-1-yl groups of formula Ar¹OH as depictedin Scheme 1:

[0163] Reaction of an optionally substituted 4-methyl-3-cyano pyridineof formula (7) with a N,N-dimethylformamide di-C₁₋₆alkyl acetal, e.g.N,N-dimethylformamide diethyl acetal, in a dipolar solvent such as anamide e.g. a substituted amide such as dimethylformamide at an elevatedtemperature e.g. 140-150° gives a compound of formula (8) or (9) or amixture thereof depending on the nature of the group R¹⁶.

[0164] Compounds of formula (8) or (9) may be cyclised to 3-substituted2,7-naphthyridin-1-yl alcohol of formula (10) by treatment with an acide.g. an inorganic acid such as hydrochloric acid or hydrobromic acid oran acidic gas such as hydrogen chloride gas in an organic solvent e.g.an organic acid such as acetic acid optionally in the presence of waterat a temperature from about ambient to 50° C.

[0165] Alternatively alkylating agents of formula Ar¹X¹ in which Ar¹represents an optionally substituted 2,7-naphthyridin-yl group may beprepared by reaction of a 2,7-naphthyridine N-oxide or N, N′-dioxidewith a halogenating agent, e.g. a phosphorous oxyhalide such asphosphorous oxychloride to give a 1-halo or 1,6-dihalo-and/or-1,8-dihalo-2,7-napthyridine respectively. In the case of1,6-dihalo- and/or 1,8-dialo-2,6-napthyridines each halogen atom may besubstituted separately by a reagent such as HL²Ar²AlkN(R¹)H orHL³(Alk²)_(t)L⁴(R⁴)_(u) by the particular methods just described above.

[0166] 2,7-Napthyridine N-oxides and N,N′-dioxides may be generated fromthe corresponding 2,7-napthyridines by the general methods of synthesisof N-oxides described below or they may be synthesised by the methods ofNumata, A. et al (Synthesis, 1999, 306-311).

[0167] Further alkylating agents of formula Ar¹X¹ in which, for example,Ar¹ represents a 2,7-naphthyridin-1-yl, may be prepared by the methodsof Wenkert E. et al J. Am. Chem. Soc. 89, 6741-5 (1967), and Aust. J.Chem. 433 (1972), and Sheffield D. J. J. Chem. Soc. Perkin. Trans I,2506 (1972).

[0168] In a further example intermediates of formula Ar¹L²Ar²AlkN(R¹)Hmay be obtained by reaction of a compound of formula Ar¹L²H with acompound of formula X¹Ar²AlkN(R¹)H under the reaction conditions justdescribed

[0169] Compounds of formula Ar¹L²H in which, for example Ar¹ representsa 2,7-naphthyridin-1-yl group and L² is a -N(R⁸)— group, may be preparedfrom substituted 4-formylpyridines by the methods of Molina, P. et alTetrahedron, 48, 4601-4616, (1992), or by the methods described in U.S.Pat. No. 3,938,367.

[0170] In another example, compounds containing a -L¹H or -L²H or groupas defined above may be functionalised by acylation or thioacylation,for example by reaction with one of the alkylating agents just describedbut in which X¹ is replaced by a —C(O)X², C(S)X², —N(R⁸)COX²or—N(R⁸)C(S)X² group in which X² is a leaving atom or group as describedfor X¹. The reaction may be performed in the presence of a base, such asa hydride, e.g. sodium hydride or an amine, e.g. triethylamine orN-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane or carbon tetrachloride or an amide, e.g.dimethylformamide, at for example ambient temperature. Alternatively,the acylation may be carried out under the same conditions with an acid(for example one of the alkylating agents described above in which X¹ isreplaced by a —CO₂H group) in the presence of a condensing agent, forexample a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideor N,N′-dicyclohexylcarbodiimide, advantageously in the presence of acatalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as1-hydroxybenzotriazole. Alternatively the acid may be reacted with achloroformate, for example ethylchloroformate, prior to the desiredacylation reaction

[0171] In a further example compounds may be obtained by sulphonylationof a compound containing an —OH group by reaction with one of the abovealkylating agents but in which X¹ is replaced by a —S(O)Hal or —SO₂Halgroup in which Hal is a halogen atom such as chlorine atom] in thepresence of a base, for example an inorganic base such as sodium hydridein a solvent such as an amide, e.g. a substituted amide such asdimethylformamide at for example ambient temperature.

[0172] In another example, compounds containing a -L¹H or -L²H group asdefined above may be coupled with one of the alkylation agents justdescribed but in which X¹ is replaced by an —OH group in a solvent suchas tetrahydrofuran in the presence of a phosphine, e.g.triphenylphosphine and an activator such as diethyl, diisopropyl- ordimethylazodicarboxylate.

[0173] In a further example, ester groups —CO₂R⁵, —CO₂R¹¹ or —CO₂Alk⁷ inthe compounds may be converted to the corresponding acid [—CO₂H] byacid- or base-catalysed hydrolysis depending on the nature of the groupsR⁵, R¹¹ or Alk⁷. Acid- or base-catalysed hydrolysis may be achieved forexample by treatment with an organic or inorganic acid, e.g.trifluoroacetic acid in an aqueous solvent or a mineral acid such ashydrochloric acid in a solvent such as dioxan or an alkali metalhydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueousmethanol.

[0174] In a further example, —OR⁵ or —OR¹⁴ groups [where R⁵ or R¹⁴ eachrepresents an alkyl group such as methyl group] in compounds of formula(1) may be cleaved to the corresponding alcohol —OH by reaction withboron tribromide in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane at a low temperature, e.g. around −78° C.

[0175] Alcohol [—OH] groups may also be obtained by hydrogenation of acorresponding —OCH₂R¹⁴ group (where R¹⁴ is an aryl group) using a metalcatalyst, for example palladium on a support such as carbon in a solventsuch as ethanol in the presence of ammonium formate, cyclohexadiene orhydrogen, from around ambient to the reflux temperature. In anotherexample, —OH groups may be generated from the corresponding ester[CO₂R¹¹ or CO₂R⁵] or aldehyde [—CHO] by reduction, using for example acomplex metal hydride such as lithium aluminium hydride or sodiumborohydride in a solvent such as methanol.

[0176] In another example, alcohol —OH groups in the compounds may beconverted to a corresponding —OR⁵ or —OR¹⁴ group by coupling with areagent R⁵OH or R¹⁴OH in a solvent such as tetrahydrofuran in thepresence of a phosphine, e.g. triphenylphosphine and an activator suchas diethyl—, diisopropyl—, or dimethylazodicarboxylate.

[0177] Aminosulphonylamino [—NHSO₂NHR² or —NHSO₂NHAr¹] groups in thecompounds may be obtained, in another example, by reaction of acorresponding amine [—NH₂] with a sulphamide R²NHSO₂NH₂ or Ar¹NHSO₂NH₂in the presence of an organic base such as pyridine at an elevatedtemperature, e.g. the reflux temperature.

[0178] In another example compounds containing a —NHCSAr¹, —CSNHAr¹,—NHCSR² or —CSNHR² may be prepared by treating a corrsponding compoundcontaining a —NHCOAr¹, —CONHAr¹, —NHCOR² or —CONHR² group with athiation reagent, such as Lawesson's Reagent, in an anhydrous solvent,for example a cyclic ether such as tetrahydrofuran, at an elevatedtemperature such as the reflux temperature.

[0179] In a further example amine (—NH₂) groups may be alkylated using areductive alkylation process employing an aldehyde and a borohydride,for example sodium triacetoxyborohyride or sodium cyanoborohydride, in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane, aketone such as acetone, or an alcohol, e.g. ethanol, where necessary inthe presence of an acid such as acetic acid at around ambienttemperature.

[0180] In a further example, amine [—NH₂] groups in compounds of formula(1) may be obtained by hydrolysis from a corresponding imide by reactionwith hydrazine in a solvent such as an alcohol, e.g. ethanol at ambienttemperature.

[0181] In another example, a nitro [—NO₂] group may be reduced to anamine [—NH₂], for example by catalytic hydrogenation using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon in a solvent such as an ether, e.g.tetrahydrofuran or an alcohol e.g. methanol, or by chemical reductionusing for example a metal, e.g. tin or iron, in the presence of an acidsuch as hydrochloric acid.

[0182] Aromatic halogen substituents in the compounds may be subjectedto halogen-metal exchange with a base, for example a lithium base suchas n-butyl or t-butyl lithium, optionally at a low temperature, e.g.around −78° C., in a solvent such as tetrahydrofuran and then quenchedwith an electrophile to introduce a desired substituent. Thus, forexample, a formyl group may be introduced by using dimethylformamide asthe electrophile; a thiomethyl group may be introduced by usingdimethyldisulphide as the electrophile.

[0183] In another example, sulphur atoms in the compounds, for examplewhen present in a linker group L¹ or L² may be oxidised to thecorresponding sulphoxide or sulphone using an oxidising agent such as aperoxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent suchas a halogenated hydrocarbon, e.g. dichloromethane, at around ambienttemperature.

[0184] In another example compounds of formula Ar¹X¹ (where X¹ is ahalogen atom such as a chlorine, bromine or iodine atom) may beconverted to such compounds as Ar¹CO₂R²⁰ (in which R²⁰ is an optionallysubstituted alkyl, aryl or heteroaryl group), Ar¹ CHO, Ar¹CHCHR²⁰,Ar¹CCR²⁰, Ar¹N(R²⁰)H, Ar¹N(R²⁰)₂, for uses in the synthesis of forexample compounds of formula Ar¹L²Ar²AlkN(R¹)H, using such well know andcommonly used palladium mediated reaction conditions as are to be foundin the general reference texts Rodd's Chemistry of Carbon Compounds,Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989),Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (JohnWiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed.Katritzky et al, Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon),Comprehensive Organic Functional Group Transformations, Ed. Katritzky etal, Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synethesis, Ed.Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia ofReagents for Organic Synthesis, Ed. Paquette, Volumes 1-8 (John Wileyand Sons, 1995), Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989) and March's Advanced Organic Chemistry (JohnWiley and Sons, 1992).

[0185] N-oxides of compounds of formula (1) may be prepared for exampleby oxidation of the corresponding nitrogen base using an oxidising agentsuch as hydrogen peroxide in the presence of an acid such as aceticacid, at an elevated temperature, for example around 70° C. to 80° C.,or alternatively by reaction with a peracid such as peracetic acid in asolvent, e.g. dichloromethane, at ambient temperature.

[0186] Salts of compounds of formula (1) may be prepared by reaction ofa compound of formula (1) with an appropriate base in a suitable solventor mixture of solvents e.g. an organic solvent such as an ether e.g.diethylether, or an alcohol, e.g. ethanol using conventional procedures.

[0187] Where it is desired to obtain a particular enantiomer of acompound of formula (1) this may be produced from a correspondingmixture of enantiomers using any suitable conventional procedure forresolving enantiomers.

[0188] Thus for example diastereomeric derivatives, e.g. salts, may beproduced by reaction of a mixture of enantiomers of formula (1) e.g. aracemate, and an appropriate chiral compound, e.g. a chiral base. Thediastereomers may then be separated by any convenient means, for exampleby crystallisation and the desired enantiomer recovered, e.g. bytreatment with an acid in the instance where the diastereomer is a salt.

[0189] In another resolution process a racemate of formula (1) may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed above.

[0190] Chromatography, recrystallisation and other conventionalseparation procedures may also be used with intermediates or finalproducts where it is desired to obtain a particular geometric isomer ofthe invention.

[0191] The following Examples illustrate the invention. All temperaturesare in 0° C. The following abbreviations are used:NMM-N-methylmorpholine; EtOAc-ethyl acetate; MeOH-methanol;BOC-butoxycarbonyl; DCM-dichloromethane; AcOH-acetic acid;DIPEA-diisopropylethylamine; EtOH-ethanol; Pyr-pyridine; Ar-aryl;DMSO-dimethylsulphoxide; iPr-isopropyl; Et₂O-diethylether; Me-methyl;THF-tetrahydrofuran, DMF-N,N-dimethylformamide;FMOC-9-fluorenylmethoxycarbonyl; TFA-trifluoroactic acid;

Intermediate 1 4-(2-(N,N-Dimethylamino)ethylen-1-yl)-3-cyanopyridine

[0192] A solution of 4-methyl-3-cyanopyridine (prepared according toRef: J. Prakt. Chem. 338, 663 (1996), 8.0 g, 67.8 mmol) andN,N-dimethylformamide diethyl acetal (11.0 g, 74.8 mmol) in dry DMF (50ml) was stirred at 140° under N₂ for 2 days. An additional portion ofN,N,-dimethylformamide diethyl acetal (5 g) was added and stirred at140° for 4 h. The volatiles were removed in vacuo and the obtained darkoil partitioned between EtOAc (300 ml) and water (50 ml). The phaseswere separated and the aqueous layer re-extracted with EtOAc (3×100 ml).The combined organic extracts were washed with brine (30 ml), dried(Na₂SO₄), treated with activated charcoal, filtered and evaporated invacuo to afford essentially pure title compound as a dull orange solid(10.1 g, 85%). δH (CDCl₃) 8.49 (1H, s), 8.25 (1h, d, J 5.9 hz), 7.29(1H, d, J 13.2 Hz), 7.09 (1H, d, J 5.9 Hz), 5.25 (1H, d, J 13.2 Hz) and2.99 (6H, s); m/z (ES⁺, 70V) 174 (MH⁺).

Intermediate 2 1-Hydroxy-2,7-naphthyridine Hydrochloride Salt

[0193] HCl gas was bubbled through a stirred solution of Intermediate 1(6.2 g, 3.58 mmol) in glacial acetic acid (50 ml) and water (0.64 ml,3.55 mmol) for 1-2 min. The reaction mixture was stirred in a stopperedflask at 40° for 18 h. The volatiles were removed in vacuo affording adark residue, which was treated with water (3×20 ml) and re-evaporatedin vacuo. The obtained dark semi-solid was treated with 40 ml warmethanol, ice-cooled, and the undissolved solid collected by filtrationaffording the title compound as a green colored solid (5.2 g, 80%) δH(DMSO-D⁶) 12.5 (1H, br s), 9.38 (1H, s), 8.84 (1H, d, J 7.0 Hz), 8.15(1H, d, J 7.0 Hz), 7.89 (1H, br dd, J 7.0, 5.0 Hz) and 6.85 (1H, d, J7.0 Hz); m/z (ES⁺, 70V), 147 (MH⁺).

Intermediate 3 1-Chloro-2,7-naphthyridine

[0194] Intermediate 2 (5.2 g, 28.5 mmol) was stirred with phosphorousoxychloride (75 ml) at 110° for 24 h. The volatiles were removed invacuo affording a dark oil which was poured into an ica-bath cooledmixture of saturated aqueous NaHCO₃ (100 ml containing 20 g solidNaHCO₃) and EtOAc (100 ml). After thorough mixing the phases wereseparated and the aqueous layer re-extracted with EtOAc (2×75 ml). Thecombined organic extracts were washed with brine (15m), dried (Na₂SO₄)and evaporated in vacuo to afford the title compound as a yellow solid(4.0 g, 85%) δH (CDCl₃) 9.45 (1H, s), 8.81 (1H, d, J 5.7 HZ), 8.47 (1H,d, J 5.7 Hz), 7.66 (1H, d, J 5.7 Hz) and 7.60 (1H, d,J 5.7 HZ); m/z(ES⁺, 70V) 165 and 167 (MH⁺).

Intermediate 4 Ethyl(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-aminopropanoate

[0195] A solution ofethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638mg, 2.07 mmol) and Intermediate 3 (310 mg, 1.88 mmol) in ethoxyethanol(2 ml) was stirred at 120° for 15 min and at 100° for 1 h undernitrogen. The volatiles were removed in vacuo and the dark residuepartitioned between EtOAc (70 ml) and saturated aqueous NaHCO₃ (10 ml).The phases were separated and the aqueous layer re-extracted with EtOAc(2×30 ml). The combined organic extracts were washed with brine (10 ml),dried (Na₂SO₄) and evaporated in vacuo to afford a dark foam.Chromatography (SiO₂; 5 to 10% MeOH/DCM) afforded a mixture ofethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl)amino]propanoate and some of the title compound (730 mg). This mixturewas treated with a solution of trifluoroacetic acid (5 ml) and DCM (5ml) at room temperature for 1 h. The volatiles were removed in vacuo andthe residue partitioned between EtOAc (75 ml) and saturated aqueousNaHCO₃ (20 ml). The phases were separated and the aqueous layerre-extracted with EtOAc (3×30 ml). The combined organic extracts werewashed with brine (10 ml), dried (Na₂SO₄) and evaporated in vacuo toafford an orange solid. Chromatography (silica; 10% MeOH/DCM) affordedthe title compound as a straw-colored solid (420 mg, 60% over twosteps). δH (CDCl₃) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz),8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz),8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz),4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz),3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V)337 (MH⁺).

Intermediate 5 Methyl-(S)-3-{(4-(3-methoxycarbonyl)-2,7-naphthyridin-1-ylamino)phenyl}-2-[(t-butoxycarbonyl)amino]propanoate

[0196] To triphosgene (187 mg, 0.63 mmol) in DCM (3.5 ml) was added asolution ofmethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino]propanate (500 mg,1.70 mmol) and iPr₂EtN (242 mg, 1.87 mmol) in DCM (6 ml) over 1 h. Aftera further 15 min the reaction was diluted with DCM (50 ml), washed (2×25ml, 0.5M HCl and 2×25ml saturated NaCl), dried (MgSO₄) and the solventremoved in vacuo to yield the crude intermediate isocyanate as a viscouspale brown oil. To the crude isocyanate (194 mg, 0.61 mol) in toluene(18 ml) was added methylβ-(4-pyridyl)-α-(triphenyl-phosphorilidenamino)acrylate (241 mg, 0.55mmol) prepared in accordance with the method described in Tetrahedron(1992), 48, 4601. The reaction was stirred at ambient temperatureovernight followed by heating at 160° in a sealed tube for 3 days. Thesolvent was removed and the soluble residues purified by chromatography(SiO₂; 50-100% EtOAc: hexane) to yield the title compound (157 mg, 59%)as a bright yellow solid. δH (CD₃OD) 9.76 (1H, s), 8.68 (1H, d, J 5.7Hz), 7.97 (2H, d, J 8.6 Hz), 7.89 (1H, s), 7.82 (1H, d, J 5.7 Hz), 7.21(2H, d, J 8.6 Hz), 4.39 (1H, m), 3.97 (3H, s), 3.71 (3H, s), 3.10 (1H,m), 2.94 (1H, m), 1.40 (9H, s); m/z (ES⁺, 70V) 480 (MH⁺).

Intermediate 6 Methyl(S)-3-L4-(2,7-naphthyridin-1-yloxy)phenyl]-2-aminopropanoate

[0197] A mixture of N-(BOC)-(S)-tyrosine methyl ester (1.71 g, 5.80(mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 3 (1.0g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18h, and at 40° for 18 h. The DMF was removed in vacuo and the residuepartitioned between EtOAc (80 ml) and 10% aqueous Na₂CO₃ (20 ml). Thephases were separated and the aqueous layer re-extracted with EtOAc(2×20 ml). The combined organic extracts were washed with brine (10 ml),dried (Na2SO₄) and evaporated in vacuo to afford a new colorless oil.Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pureN--butoxycarbonyl protected title compound (1.75 g, 71%). This materialwas dissolved in EtOAc (40 ml) and HCl gas was bubbled through thestirred solution for 1 min. then the mixture was stirred for anadditional 0.5 h. The volatiles were removed in vacuo affording a yellowsolid which was partitioned between EtOAc (80 ml) and saturated aqueousNaHCO₃ (20 ml). The phases were separated and the aqueous layerre-extracted with EtOAc (2×20ml). The combined organic extracts werewashed with brine (10 ml), dried (Na₂SO₄) and evaporated in vacuo. Theobtained oil was chromatographed (silica; 5% MeOH/DCM) to afford thetitle compound as a near colorless oil (0.83 g, 62%) δH (CDCl₃) 9.77(1H. s), 8.75 (1H, d, J 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1H, d, J 5.9 Hz), 7.21 (2H, d, J8.4 Hz), 3.80-3.70 (1H, obscured m), 3.72 (3H,s ), 3.15 (1H, dd, J 13.6,5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) and 0.78 (2H, br s); m/z (ES⁺,70V) 324 (MH⁺).

Intermediate 7 4-Acetonyl-3-cyanopyridine

[0198] A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) andN,N-dimethylacetamide dimethylacetyl (5.4 g, 40.6 mmol) in dry DMF(20ml) was stirred at 130° for 7 h. The volatiles were removed in vacuoto afford a dark oil which solidified on standing. This material waschromatographed (silica; 50% EtOAcl Hexane-100% EtOAc) affording thetitle compound as an off-yellow solid (3.73 g, 69%). δH (CDCl₃) 8.87(1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s)and 2.36 (3H, s); m/z (ES⁺, 70V) 161 (MH⁺).

Intermediate 8 1-Hydroxy-3-methyl-2,7-naphthyridine Hydrochloride

[0199] HCl gas was bubbled through a stirred solution of Intermediate 7(3.73 g, 23.3 mmol) in glacial acetic acid (40 ml) for several minutes.The flask was stoppered and reaction stirred for 18 h at ambienttemperature. The volatiles were removed in vacuo affording astraw-colored solid. This was twice treated with water (30 ml portions)and re-evaporated in vacuo to dryness, affording the title compound(contaminated with 25% unidentified by-product) as a dark straw coloredsolid (4.1 g). δH (DMSO-d⁶) 12.46 (1H, br s), 9.32 (1H,s ), 8.71 (1H, d,1 6.5 Hz), 7.98 (1H, d, J 6.5 Hz), 6.67 (1H,s) and 2.38 (3H, s); m/Z(ES⁺, 70V) 161 (MH⁺). Used without further purification.

Intermediate 9 1-Chloro-3-methyl-2,7-naphthyridine

[0200] Intermediate 8 (4.1 g) was treated with phosphorus oxychloride(50 ml) at 130° for 3 h, affording a dark solution. The volatiles wereremoved in vacuo and the obtained dark oil extracted with Et₂O (100 ml).Saturated aqueous NaHCO₃ (ice cold; containing 10 g additional solidNaHCO₃) was poured (with CARE!) onto the crude product with swirling andice-bath cooling. After thorough shaking, addition Et₂O (80 ml) wasadded, the mixture re-shaken, and the phases separated. The aqueouslayer was re-extracted with Et₂O (2×80 ml) and the combined etherealextracts washed with brine (20 ml), dried (Na2SO₄) and evaporated invacuo to afford an orange solid (3.6 g). Chromatography (silica; 70%EtOAc/Hexane-100% EtOAc) afforded a more-polar by-product(3-methyl-1H-pyrano[3,4-C]pyridin-1-one, (0.7 g) and the title compoundas a white solid (2.82 g, 79% from intermediate 7) δH (CDCl₃) 9.66 (1H,s), 8.73 (1H, d, J 5.8 hz), 7.56 (1H, d, J 5.8 Hz), 7.40 (1H, s) and2,69 (3H, s); m/ (ES⁺, 70V) 179 and 181 (MH⁺).

Intermediate 10 Ethyl)-3-[4-(3-methyl-2.7-naphthyridin-1-ylamino)phenyl]-2[-N-(tertbutyloxycarbonyl)amino]propanoatehydrochloride

[0201] Acetylchloride (55 mg, 50 ml, 0.70 mmol) was added to absoluteethanol (25 ml) and stirred for one minute. Intermediate 9 (2.50 g, 14.0mmol) andethyl-(S)-3-[4-aminophenyl]-2-{tert-butyloxycarbonyl]propanoate (4.31 g,14.0 mmol) were added and the reaction mixture stirred at 60° for 2.75h. The volatiles were removed in vacuo to afford a yellow-orange solid.This was treated with EtOAc (˜25 ml), warmed, re-cooled and theprecipitate collected by filtration, with Et₂O washing, affording thetitle compound as yellow solid (4.96 g, 73%). δH (CDCl₃) 10.44 (1 h, brs), 10.33 (1H, br s), 8.60 (1H, d, J 6.5 Hz), 8.00 (1H, d, . 6.5 Hz),7.85 (2H, d, J 8.5Hz), 7.28 (1H, d, J 8.0 Hz), 7.23 (2H, d, J 8.5 Hz),7.16 (1H,s ), 4.19-4.01 (1H, m), 4.08 (2H, q, J 7.0 Hz), 2.97 (1H, dd, J13.8, 5.4 Hz), 2.86 (1H, dd, J 13.8, 10.0 Hz), 2.50 (3H,s ), 1.34 (9H,s) and 1.15 (3H, t, J 7.0 Hz); m/z (ES⁺, 70V)451 (MH⁺).

Intermediate 11Ethyl-(S)-3-[4-3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-aminopropanoate

[0202] HCl gas was bubbled through a stirred solution of Intermediate 10(4.95 g, 10.2 mmol) for 1-2min. After 30 min stirring at ambienttemperature the volatiles were removed in vacuo affording a yellowpowder. This was treatd with saturated aqueous NaHCO₃ (30 ml) thenextracted with EtOAc (100 ml, and 3×50 ml). The combined organicextracts were washed with brine (10 ml), dried (Na₂SO₄) and evaporatedin vacuo affording the title compound as a yellow solid (3.56, 100%). δH(CDCl₃) 9.25 (1H, s), 8.50 (1H, d, J 5.6 Hz), 7.66 (2H, d, 1 8.4 Hz),7.35 (1H, d, J 5.6 Hz), 7.34 (1H, masked s), 7.14 (2H, d, J 8.4 Hz),6.81 (1H, s), 4.12 (2H, q, J 7.2 Hz), 3.65 91H, dd, J 7.8, 5.2 Hz), 3.02(1H, dd, J 13.7, 5.2 Hz), 2.80 (1H, dd, J 13.7, 7.8 Hz), 2.48 (3H, s),1.56 (2H, br s) and 1.21 (3H, t, J 7.2 Hz); m/z (ES⁺, 70V) 351 (MH⁺).

Intermediate 12 Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(N-t-butyloxycarbonylamino)propanoate

[0203] A mixture of N-t-butyloxycarbonyl-(S)-tyrosine methyl ester (2.55g, 8.64 mmol) caesium carbonate (2.81 g, 8.62 mmol) and Intermediate 9(140 g, 7.84 mmol) in dry DMF (30 ml) was stirred at room temperaturefor 2 days. The volatiles were removed in vacuo and the residuepartitioned between EtOAc (100 ml) and 10% aqueous NH₄Cl solution. Theaqueous layer was re-extracted with EtOAc (50 ml). The combined organicextracts were washed with brine (15 ml), dried (Na₂SO₄) and evaporatedin vacuo to afford an oil (4.1 g). Chromatography (silica; 50%-70%EtOAc/Hexane) afforded the title compound as a white foam (3.1 g, 90%).δH (DMSO-d⁶) 9.59 (1H, s), 8.72 (1H, d, J 5.7 Hz), 7.75 (1H, d, J 5.7Hz), 7.37 (1H, br s), 7.36 (1H, d, J 5.7 Hz), 7.23 (2H, d, J 8.5 Hz),4.23 (1H, m), 3.64 (3H, s), 3.05 (1H,dd, J 13.8, 5.1 Hz), 2.92 (1H, dd,J 13.8,10.1 Hz), 2.37 (3H,s ) and 1.36 (9H, s); m/z (ES⁺, 70V) 438(MH⁺).

Intermediate 13 Methyl (S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-aminopropanoate Dihydrochloride

[0204] HCl gas was bubbled through a stirred solution of intermediate 12(3.1 g, 7.09 mmol) in EtOAc (60 ml) for approximately one minute. Thereaction mixture was stirred at ambient temperature for 0.5 h then thevolatiles were removed in vacuo to afford the title compound as a whitepowder (3.0 g, 100%) which was used immediately without furtherpurification. δH (DMSO-d⁶) 9.93 (1H,s ), 8.86 (1H,d, J 6.5 Hz), 8.34(1H, d, J 6.5 Hz), 7.68 (1H,s ), 7.39 (2H, d, J 8.6 Hz), 7.34 (2H, d, 18.6 Hz), 4.28 (1H, m), 3.68 (3H, s), 3.32 (1H, dd, J 14.0, 5.6 Hz), 3.17(1H, dd, J 14.0, 7.9 Hz) and 2.49 (3H, s); m/z (ES⁺, 70V) 338 (MH⁺).

Intermediate 14 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(N-tbutyloxycarbonylamino)-propanoate

[0205] A mixture of N-t-butyloxycarbonyl-(S)-tyrosine ethyl ester (14.5g, 46.9 mmol), caesium carbonate (14.05 g,43.1 mmol) and Intermediate 9(7.0 g, 39.2 mmol) in dry DMF (60 ml) was stirred at room temperaturefor 48 h. The reaction was diluted with Et₂O (150 ml) and filtered off.The filtrate was evaporated under high vacuum and the residue waschromatographed (SiO₂; 40%-60% EtOAc/Hexane) which afforded the titlecompound as a viscous, straw-colored oil (16.2 g, 77%) δH (CDCl₃) 9.56(1H, s), 8.58 (1H, d, J 5.8 Hz), 7.39 (1H, d, J 5.8 Hz), 7.15-7.10 (4H,m), 7.00 (1H, s), 4.99-4.91 (1H,m), 4.54-4.46 (1H, m), 4.09 (2H, q, J7.1 Hz), 3.10-2.99 (2H,m), 2.36 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J7.1 Hz); m/z (ES⁺, 70V) 452 (MH⁺).

Intermediate 15 Ethyl(S)-3-[4-(3-methyl-2.7-naphthyridin-1-yloxy)phenyl-]2-aminopropanoate

[0206] HCl gas was bubbled through a stirred solution of Intermediate 14(16 g) in EtOAc (300 ml) until a persistent fine white precipitateformed (˜2minutes). After stirring for 0.5 h the volatiles were removedin vacuo. The obtained solid was partitioned between EtOAc (250 ml) andsaturated aqueous NaHCO₃ (80 ml plus 5 g solid NaHCO₃). The phases wereseparated and the aqueous layer re-extracted with EtOAc (5×50 ml). Thecombined organic extracts were washed with brine (10 ml), dried (Na₂SO₄)and evaporated in vacuo to afford an oil Chromatography (SiO₂; 100%EtOAC-10% EtOH/EtOAc) afforded the title compound as a viscous oil (11g, 89%). δH (CDCl₃) 9.71 (1H,s ), 8.70 (1H, d, J 5. Hz), 7.50 (1H, d, J5.8 Hz), 7.31-7.28 (4H,m), 7.11 (1H, s), 4.23 (2H, q, J 7.1 Hz),3.79-3.72 (1H, m), 3.14 (1H, dd, J 14.1, 5.4 Hz), 2.94 (1H, dd, J 14.1,7.8 Hz), 2.47 (3H, s), 1.75-1.50 (2H, br s) and 1.30 (3H, t, J 7.1 Hz);m/z (ES⁺, 70V) 352 (MH⁺).

Intermediate 16 3-Trifluoromethyl-2,7-naphthyridone

[0207] To a rapidly stirred suspension of 4-methylnicotinic acid HCl(952 mg, 5.48 mmol) in THF (25 ml) at −78° was added n-butyl lithium(17.0 mmol) over 20 min, maintaining the temperature below −50°. Thereaction was maintained at −78° for 1.5 h, the temperature raised to−30° and after 40 min CO₂ gas bubbled through the solution for 10 minmaintaining the temperature between −30 to −20°. The reaction was thenallowed to warm to ambient temperature, poured into water (30 ml) and tothis was added 1M HCl (30 ml). The solution was washed with DCM (2×20ml) and the aqueous layer concentrated in vacuo at a temperature below50° to give crude 4-(carboxymethyl)nicotinic acid as a brown oil. m/Z(ES⁺, 70V) 182 (MH⁺). The brown oil was dissolved in trifluoroaceticanhydride (15 ml) and after 10 min heated at 100° in a sealed tube for 4days. The solvent was removed under vacuum and the resulting crude3-(trifluoromethyl)-1H-pyrano[3,4-C]pyridin-1-one, m/z (ES⁺, 70V) 216(MH⁺) dissolved in concentrated NH₄OH (10 ml) and heated at 100° for 1h, additional concentrated NH₄OH (10 ml) added after 20 and 40 minutes.The reaction was allowed to cool to ambient temperature, and the palebrown aqueous solution separated. The organic layer was separated andconcentrated in vacuo to yield a brown/orange oily solid purified bycolumn chromatography (SiO₂:EtOAc) to give the title compound (957 mg,82%) as a pale yellow solid. δH (DMSO-d⁶) 9.24 (1H, s), 8.71 (1H, d, J5.4 Hz), 7.65 (1H, d J 5.4 Hz), 7.11 91H, s), 3.19 (1H, br s). m/z (ES⁺,70V), 215 (MH⁺).

Intermediate 17 3-Trifluoromethyl)-1-chloro-2,7-naphthyridine

[0208] Intermediate 16 (892 mg) was heated at 125° for 5 h in POCl₃ (10ml). The solvent was removed in vacuo to give a brown/orange solid whichwas suspended in rapidly stirring, ice-cooled DCM (30 ml). Saturated,ice-cooled NaHCO₃ (20 ml) was rapidly added to the stirring suspension,the DCM layer separated, the aqueous layer was then extracted with DCM(3×20 ml). The combined DCM layers were washed with saturated brine,dried (MgSO₄) and concentrated in vacuo to give the crude title compound(343 mg) contaminated with starting material. δH (DMSO-d⁶) 9.78 (1H, s),9.04 (1H, d, J 5.7 Hz), 8.64 (1H, s), 8.20 (1H, d, J 5.6 Hz). m/Z (ES⁺,70V) 233 (MH⁺).

Intermediate 18Ethyl-(S)-3-{4-[(3-trifluoromethyl)-2.7-naphthyridin-1-yloxy]phenyl}-2-[t-butoxycarbonylamino]propanoate

[0209] To N-tBOC-(S)-tyrosine ethyl ester (296 mg, 0.96 mmol) in DMF (5ml) were added caesium carbonate (328 mg, 1.01 mmol) and crudeIntermediate 17 (234 mg, 1.01 mmol). The reaction was heated at 45° for18 h then 7 h at 60°. The solvent was removed in vacuo and the residuepurified by chromatography (SiO₂.30% EtOAc/Hexane) to give the titlecompound (288 mg, 60%) as a pale yellow glass. δH (CD₃OD) 7.64 (1H,s ),8.72 (1H, d, J 5.8 Hz), 7.85 (1H, d, J 5.8 Hz), 7.80 (1H, s), 7.19 (2H,d, J 8.6 Hz), 7.12 (2H, d, J 8.6 Hz), 4.24 (1H, m), 3.98 (2H, q, 1 7.1Hz), 2.99 (1H, dd, J 13.7, 6.1 Hz), 2.84 (1H, dd, 1 13.7, 8.6 Hz), 1.25(9H, s), 1.06 (3H, t, J 7.1 Hz). m/z (ES⁺, 70V) 528 (MNa⁺).

Intermediate 19 1-Chloro-3-ethyl-2,7-naphthyridine

[0210] Prepared in a similar manner to the compound of Intermediate 9.δH (DMSO-d⁶) 9.65 (1H, s), 8.88 (1H, d, J 5.7 Hz), 7.99 (1H, d, J 5.7Hz), 7.82 (1H, s), 2.97 (2H, q, J 7.5 Hz), 1.39 (3H, t, J 7.5 Hz); m/z(ES+70V) 193 (MH⁺).

Intermediate 20 1-Chloro-3-iso-butyl-2,7-naphthyridine

[0211] The title compound was prepared in a similar manner to thecompound of Intermediate 9. δH (CDCl₃) 9.68 (1H, s), 8.75 (1H, d, J 5.7Hz), 7.59 (1H, d, J 5.7 Hz), 7.37 (1H, s ), 2.78 (2H, d, J 7.2 Hz), 2.25(1H, septet, J 6.7 Hz) and 0.96 (6H, d, J 6.7 Hz); m/z (ES⁺, 70V) 221and 223 (MH⁺).

Intermediate 21 Ethyl3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-(t-butyloxy-carbonylamino)propanoate

[0212] The compound of Intermediate 9 (1.5 g, 8.4 mmol) was added to asolution of ethyl-3-(4-aminophenyl)-3-(t-butyloxycaronylamino)propanoate(2. 59 g, 8.4 mmol) [prepared according to the methods of InternationalPatent Application WO 00/32575] in 2-ethoxyethanol (20ml) and heated to100° for 5 h. The mixture was concentrated in vacuo to give a dark brownsolid that was used without further purification.

Intermediate 22 Ethyl3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-amino propanoate

[0213] The compound of Intermediate 21 was treated with a 3M solution ofHCl in EtOAc for 2 min. The mixture was then concentrated in vacuo andused without further purification.

EXAMPLE 1 Ethyl (S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[2-isopropoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0214] A solution of Intermediate 4 (410 mg, 1.22 mmol) and1,2-diisopropoxy-3,4-dioxocyclobut-1-ene (290 mg, 1.46 mmol) in absoluteethanol (20 ml) was stirred at 50° overnight. The ethanol was removed invacuo and replaced with isopropanol (10 ml) and the reaction mixtureheated at 70° for 5 h. The volatiles were removed in vacuo and theresidue chromatographed (silica; 2 to 5% MeOH/DCM) affording the titlecompound a straw-colored foam (455 mg, 79%). δH (CDCl₃) 9.43 (1H, s),8.65 (1H, d, J 5.6 Hz), 8.19 (1H, d, J 5.7 Hz), 7.66 (2H, d, J 8.4 Hz),7.65 (1H, masked s), 7.52 (1H, d, J 5.6 Hz), 7.13 (2H, d, J 8.4 Hz),7.03 (1H, d, J 5.7 Hz), 6.72, 6.01, 5.18 and 4.63 (together 1H, br m),5.36 (1H, m), 4.26 (2H, q, J 7.1 Hz), 3.29-3.08 (2H, br m), 1.41 (3H, d,J 7.1 Hz), 1.40 (3H, d, J 7.1 HZ) and 1.31 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 475 (MH⁺).

EXAMPLE 2 Ethyl(S)-3-[4-(2.7-naphthyridin-1-ylamino)phenyl]-2-[2-ethoxy-3.4-dioxocyclobut-1-enylamino]propanoate

[0215] Prepared from Intermediate 4 and1,2-diethoxy-3,4-dioxocyclobut-1-ene in a similar manner to Example 1 togive the title compound (1.14 g, 90%) as a yellow glass. δH (CD₃OD) 9.45(1H, s), 8.37 (1H,d, J 5.7 Hz), 7.90 (1H, d, J 5.8 Hz), 7.46 (3H, m),7.04 (2H, d, J 8.4 Hz), 6.90 (1H, d, J 5.9 Hz), 4.90, 4.50 (1H, s x m),4.48 (2H, m), 4.06 (2H, m), 3.14 (1H, m), 2.80 (1H, m), 1.22 (3H, t),1.11 (3H, t); m/z (ES⁺, 70V, 461 (MH⁺).

EXAMPLE 3 Ethyl(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0216] A solution of the compound of Example 1 (305 mg, 0.64 mmol) anddiethylamine (0.193 μl, 136 mg, 1.86 mmol) in ethanol (10 ml) wasstirred at 50° for 18 h. The volatiles were removed in vacuo and theresidue chromatographed (silica; 3% EtOH/EtOAc) to afford the titlecompound as a pale yellow foam (290 mg, 93%). δH (DMSO-d⁶, 340K), 9.82(1H, s), 9.38 (1H, s), 8.65 (1H, d, J 5.6HZ), 8.16 (1H, d, J 5.7 Hz),7.78 (2H, d, J 8.55 Hz), 7.65 (1H, d, J 5.7 Hz), 7.45 (1H, br s), 7.24(2H, d, J 8.6 Hz), 7.10 (1H, d, J 5.75 Hz), 5.22 (1H, narrow m), 4.19(2H, q, J 7.1 Hz), 3.55 (4H, q, J 7.1 Hz), 3.25 (1H, dd, J 14.1,5.0 Hz),3.06 (1H, dd, J 14.1, 4.11 Hz), 1.24 (3H, t, J 7.09 Hz) and 1.14 (6H, t,J 7.13 Hz); m/z (ES⁺, 70V) 488 (MH⁺).

EXAMPLE 4(S)-3-[4-(2.7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0217] The compound of Example 3 (290 mg, 0.06 mmol) was treated withLiOH.H₂O (39 mg, 0.093 mmol) in dioxan (3 ml) and water (3 ml) at roomtemperature for 1.5 h. The volatiles were removed in vacuo and theresidue chromatographed [silica; DCM (200 to 120) MeOH (20), AcOH (3),H₂O (2)] to afford a yellow oil, that was freeze-dried from aqueousmethanol to give the title compound as a bright yellow amorphous powder(198 mg, 71%). δH (d₆ DMSO, 350K) 9.81 (1H, s), 9.34 (1H, br s), 8.64(1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.77 (2H, d, J 8.3 Hz), 7.64(1H, dd, J 5.6, 0.9 Hz), 7.30 (1H, br d, J 8.0 Hz), 7.24 (1H, d, J 8.3Hz), 7.09 (1H, d, J 5.7 Hz), 5.14-5.10 (1H, m), 3.60-3.49 (4H, m), 3.26(1H, dd, J 14.1, 4.8 Hz), 3.08 (1H, dd, J 14.1, 9.7 Hz), 1.15 (6H, t, J7.1 Hz); m/z (ES⁺, 70V) 460 (MH⁺).

EXAMPLE 5(S)-3[4-(2,7-Naphthyridin-1-ylamino)phenyl]2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicAcid

[0218] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 1 and dipropylamine to give the title compound.δH (d₆ DMSO, 350K) 9.81 (1H, s), 9.37 (1H, br s), 8.64 (1H, d, J 5.6HZ),8.15 (1H, d, J 5.6 Hz), 7.77 (2H, d, J 8.2 Hz), 7.62 (1H, dd, J 5.6, 0.8Hz), 7.29 91H, d, J 7.1 Hz), 7.22 (2H, d, J 8.2 Hz), 7.10 (1H, d, J 5.6Hz), 5.11-5.07 (1H, narrow m), 3.58-3.46 (2H, m), 3.44-3.37 (2H, m),3.26 (1H, dd, J 14.0, 4.7 Hz), 3.08 (1H, dd, J 14.0, 9.7 Hz), 1.58-1.49(4H, m), 0.85 (6H, t, J 7.3 Hz); m/z (ES⁺, 70V) 488 (MH⁺).

EXAMPLE 6(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2.5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicAcid

[0219] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 1 and cis-2,5-dimethylpyrrolidine to give thetitle compound. δH (DMSO-d⁶) 9.82 (1H, s), 9.52 (1H, S), 8.65 (1H, d, J5.6 Hz), 8.16 (1H, d, J 5.7 Hz), 7.76 (2H, d, J 8.5 Hz), 7/68 (1H, d, J5.6 Hz), 7.53 (1H, d, J 7.0 Hz), 7.24 (1H, d, J 8.5 Hz), 7.12 (1H, d, J5.7 Hz), 5.06 (1H, m), 4.18 (2H, m), 3.24 (1H, dd, J 13.0, 4.1 Hz), 3.04(1H, dd, J 13.9, 10.7 Hz), 2.08 (2H, m), 1.67 (2H, m), 1.25 (3H, d, J6.4 Hz) and 1.21 (3H, d, J 6.3 Hz); m/z (ES⁺, 70V) 486 (MH⁺).

EXAMPLE 7 Ethyl(S)-3-[4-(2.7-naphthyridin-1-ylamino)phenyl]-2-[2-(2-methyl-piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0220] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 1 and 2-methylpiperidine to give the titlecompound δH (DMSO-d⁶) 9.81 (1H, s), 9.51 (1H, s), 8.64 (1H, d, J 5.6Hz), 8.14 (1H, d, J 5.8 Hz), 7.89-7.76 (3H, m), 7.67 (1H, d, J 5.53 Hz),7.22-7.19 (2H, m), 7.11 (1H, d, J 5.8 Hz), 5.16 (1H, m), 4.45 (1H, m),4.15 (2H, d, J 7.1 Hz), 4.1-3.9 (2H, m), 3.2-2.9 (2H, m), 1.7-1.3 (6H,m) and 1.3-1.1 (6H, m). m/z (ES⁺, 70V) 514 (MH⁺).

EXAMPLE 8 (S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(2-methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid

[0221] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 7. δH (DMSO-d⁶, 350K), 9.87 (1H, s), 9.39 (1H,s), 8.70 (1H, d, J 5.6 Hz), 8.21 (1H, d, J 5.6 Hz), 7.83 (2H, d, J 8.4Hz), 7.7 (1H, d, J 5.6 Hz), 7.48 (1H, d, J 7.6 Hz), 7.20 (2H, d, J 8.5Hz), 7.14 (1H, d, J 5.7 Hz), 5.18 (1H, m), 4.51 (1H, m), 4.10 (1H, m),3.36-3.07 (2H, m), 3.1-2.9 (1H, m), 1.87-1.47 (6H, m) and 1.29 (3H, d, J6.85 Hz); m/z (ES⁺, 70V); 486 (MH⁺).

EXAMPLE 9 Ethyl(S)-3-[4-2,7-naphthyridin-1-ylamino)phenyl]-2-[(2-pyrrolidin-1-yl-3.4-dioxocyclobut-1-enyl)amino]propanoate

[0222] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 1 and pyrrolidine to give the title compound asan orange solid. δH (CDCl₃) 9.43 (1H, br s), 8.66 (1H. d, J 5.6 Hz),8.20 (1H, d, J 5.7 Hz), 7.69-7.51 (4H, m), 7.10 (2H, d, J 8.4 Hz), 7.04(1 H, d, J 5.7 Hz), 5.49 (1H, br m), 5.33-5.30 (1H, m), 4.23 (2H, q, J7.0 Hz), 3.75-3.63 (4H, br m), 3.25-3.20 (2H, m), 1.98-1.93 (4H, m) and1.23 (3H, t, J 7.0 Hz). m/z (ES⁺, 70V) 487 (MH⁺).

EXAMPLE 10(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[(2-pyrrolidin-1-yl-3,4-dioxocyclobut-1-enyl)amino]propanoicacid

[0223] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 9. δH (DMSO-d⁶), 9.82 (1H, s ), 9.38 (1H, br s),8.64 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.75 (2H, d, J 8.3 Hz),7.64 (1H, d, J 5.6 Hz), 7.35 (1H, br s), 7.23 (2H, d, J 8.4 Hz), 7.08(1H, d, J 5.7 Hz), 4.94-4.92 (1H, m), 3.68-3.62 (4H, m), 3.27-3.20 (1H,m), 3.11-3.06 (1H, m), 1.92 (3H, s) and 1.89-1.86 (4H, m). (ES⁺, 70V)458 (MH⁺).

EXAMPLE 11 Methyl(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(2-methylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0224] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 1 and 2-methylpyrrolidine. δH (DMSO-d⁶) 9.88(1H, s), (9.59 (1H, s), 8.72 (1H, d, J 5.6 Hz), 8.21 (1H, d, J 4.7 Hz),7.86 (3H, m), 7.29 (2H, d, J 8.3 Hz), 7.18 (1H, d, J 5.8 Hz), 5.20 (1H,m), 4.29 (1H, m), 3.89 (1H, m), 3.60 (1H, m), 3.35 (3H, s), 3.31 (1H,m), 3.01 (1H, m), 2.05 (3H, br m), 1.67 (1H, m) and 1.17 (3H, br m). m/z(ES⁺, 70V) 486 (MH⁺).

EXAMPLE 12(S)-3-[4-(2.7-Naphthyridin-1-ylamino)phenyl]-2-[2-(2-methylpyrrolidin-1yl)-3,4-dioxocycylobut-1-enylamino]propanoicacid

[0225] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 11. 5H (DMSO-d⁶), 9.88 (1H, s), 9.58 (1H, m),8.71 (1H, d, J 5.6 Hz), 8.21 (1H, d, J 7.1 Hz), 7.84-7.74 (3H, m), 7.29(2H, d, J 8.5 Hz), 7.18 (1H, d, J 5.8 Hz), 5.13 (1H, m), 4.33 (1H, m),3.89 (1H, m), 3.57 (1H, m), 3.27 (1H, m), 3.06 (1H, m), 2.09-1.92 (3H,br m), 1.68 (1H, m) and 1.18 (3H, br m). m/z (ES⁺, 70V) 472 (MH⁺).

EXAMPLE 13 Ethyl(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0226] Prepared in a manner similar to Example 3 from the compound ofExample 1 and trans-2,5-dimethylpyrrolidine to give the title compoundas a pale yellow solid. δH (DMSO-d⁶, 340K), 9.82 (1H, s), 9.38 (1H, s),8.64 (1H, d, J 5.6 Hz), 8.16 (1H, d, J 5.7 Hz), 7.79 (2H, d, J 8.6 Hz),7.65 (1H, d, J 5.7 Hz), 7.41 (1H, d, J 8.9 Hz), 7.24 (2H, d, J 8.6 Hz),7.11 (1H, d, J 5.6 Hz), 5.22 (1H, m), 4.38 (2H, m), 4.21 (1H, m), 4.17(2H, q, J 7,0 Hz), 3.48 (1H, m), 3.26 (1H, dd, J 14.3, 5.5 Hz), 3.14(1H, dd, J 14.3, 9.5 Hz), 2.14 (2H, m), 1.59 (2H, m), 1.22 (3H, t, J 7.1Hz) and 1.10 (6H, d, J 6.5 Hz) m/z (ES⁺, 70V) 514 (MH⁺).

EXAMPLE 14(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic

[0227] Prepared in a manner similar to Example 4 from the compound ofExample 13 to give the title compound as a pale yellow solid. δH(DMSO-d⁶, 340K), 9.81 (1H, s), 9.37 (1H, s), 8.64 (1H, d, J 5.8 Hz),8.15 (1 H, d, J 5.8 Hz), 7.76 (2H, d, J 8.6 Hz), 7.64 (1H, d, J 5.8 Hz),7.23 (2H, d, J 8.6 Hz), 7.10 (1H, d, J 5.8 Hz), 5.08 (1H, m), 4.36 (2H,m), 3.24 (1H, m), 3.08 (1H, m), 2.15 (2H, m), 1.59 (2H, m), 1.11 (6H, d,J 6.5 Hz). m/z (ESI, 70V) 486 (MH⁺).

EXAMPLE 15Ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[2-piperidin-1-Yl-3,4-dioxocyclobut-1-enylamino]propanoate

[0228] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 1 and piperidine. δH (CDCl₃), 9.89 (1H, s), 9.5991H, s), 8.71 (1H, d, J 5.6 Hz), 8.22 (1H, d, J 5.7 Hz), 7.82 (2H, m),7.75 (1H, d, J 5.6 Hz), 7.28 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.7 Hz),5.22 (1H, dd, J 10.5, 4.7 Hz), 4.26-4.20 (2H, m), 3.28 (1H, dd, J 4,74.7 Hz), 3.07 (1H, dd, J 13.8, 10.6 Hz), 2.56 (4H, m), 1.80-1.51 (6H, m)and 1.28 (3H, t, J 7.1 Hz), m/z (ES⁺, 70V) 500 (MH⁺).

EXAMPLE 16(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-piperidin-1-yl-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0229] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 15. δH (DMSO-d⁶), 9.86 (1H, s), 9.44 (1H, s),8.65 (1H, d, J 5.6 Hz), 8.16 (1H, d, J 5.7 Hz), 7.97-7.77 (2H, m),7.67-7.64 (2H, m), 7.24-7.21 (2H, m), 7.13 (1H, d, J 5.7 Hz), 5.02 (1H,br s), 3.63 (4H, br s), 3.23 (1H, dd, J 13.9, 4.2 Hz), 3.02 (1H, dd, J13.9, 4.49 Hz) and 1.68-1.52 (6H, m). m/z (ES⁺, 70V) 472 (MH⁺).

EXAMPLE 17Ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0230] Prepared from the compound of Example 2 in a manner similar tothat for the compound of Example 3 and azepane to give the titlecompound as a yellow glass. δH (CD₃OD) 9.66 (1H, s), 8.59 (1H, d, J 5.7Hz), 8.12 (1H, d, J 5.8 Hz), 7.69 (3H, m), 7.27 (2H, d, J 8.4 Hz), 7.11(1H, d, J 5.7 Hz), 5.35 (1H, m), 4.28 (2H, q, J 7.2 Hz), 4.1-3.5 (4H, 2x br), 3.41 (1H, dd, J 14.0, 4.7 Hz), 3.08 (1H, dd, J 14.0, 10.6 Hz),1.74 (4H, br s), 1.59 (4H, br s), 1.33 (3H, t, J 7.1 Hz). m/z (ES⁺, 70V)514 (MH⁺).

EXAMPLE 18(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]proanoicacid

[0231] Prepared from the compound of Example 17 in a similar manner toExample 4 to give the title compound as a yellow solid. δH (DMSO-d⁶,350K) 9.83 (1H, s), 9.35 (1H, s), 8.66 (1H, d, J 5.6 Hz), 8.17 (1H, d, J5.7 Hz), 7.79 (2H, d, J 8.3 Hz), 7.66 (1H. d, J 5.7 Hz), 7.30 (1H, d, J7.25 Hz), 7.25 (2H, d, J 8.6 Hz), 7.11 (1H, d, J 5.6 Hz), 5.14 (1H, m),3.67 (4H, m), 3.27 (1H, dd, J 14.2, 5.0 Hz), 3.10 (1H, dd, J 14.2, 9.8Hz), 1.68 (4H, br), 1.54 (4H, m). m/z (ES⁺, 70V) 486 (MH⁺).

EXAMPLE 19 Methyl(S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-[2-isopropoxy-3,4-dioxocyclobut-1-enyl]propanoate

[0232] A solution of Intermediate 6 (870 mg, 2.69 mmol) and1,2-diisopropoxy-3,4-dioxocyclobut-1-ene (587 mg, 2.96 mmol) in methanol(10 ml) was stirred at 70° for 18 h. The volatiles were removed in vacuoand the obtained oil chromatographed (SiO₂; 50% EtOAc/Hexane -100%EtOAc) to afford the title compound as a white foam (850 mg, 68%). δH(CDCl₃) 9.79 (1H, s), 8.78 (1H, d, J 5.7 Hz), 8.11 (1H, d, J 5.8 Hz),7.61 (1H, d, J 5.8 Hz), 7.28 (1H, d, J 5.9 Hz), 7.28-7.22 (5H, m), 6.44,5.89, 5.20 and 4.66 (together 1H, br s), 5.38 (1H, m), 3.82 (3H, s),3.34-3.13 (2H, br m), 1.43 (3H, d, J 6.2 Hz) and 1.41 (3H, d, J 6.2 Hz);m/z (ES⁺, 70V) 462 (MH⁺).

EXAMPLE 20Ethyl-(S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-[2-ethoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0233] A solution of N-tbutoxycarbonyl-(S)-tyrosine ethyl ester (5 g,16.2 mmol) in DMF (80 ml) was treated with caesium carbonate (5.36 g)and the compound of Intermediate 3 (2,7 g) and stirred at roomtemperature for 16 h then concentrated and purified by chromatography(SiO₂; EtOAc). The product was dissolved in EtOAc and treated withexcess HCl gas and the white precipitate isolated by filtration anddried, dissolved in ethanol (100 ml) and treated with Hunigs base (5.94ml), 1,2-diethyoxy-3,4-dioxocyclobut-1-ene and stirred at roomtemperature for 16 h. The solution was concentrated in vacuo thenpurified by chromatography (SiO₂; EtOAc/hexane 1:4-1:2) to give thetitle compound (4.5 g, 60%) as a white foamy solid. δH (DMSO-d⁶, 350K),9.71 (1H, s), 8.81 (1H, d, J 5.8 Hz), 8.15 (1H, d, J 5.8 hz), 7.86 (1H,dd, J 8.1, 1.0 Hz), 7.53 (1H, dd, J 5.8, 1.0 Hz), 7.36 (2H, d, J 8.7Hz), 7.26 (2H, d, J 8.7 Hz), 4.65 (2H, qd, J 7.1, 1.1 Hz), 4.20 (2H, q,J 7.05 Hz), 3.31 (1H, dd, J 14.1, 5.1 Hz), 3.11 (1H, dd, J 14.1, 9.8Hz), 1.39 (3H, t, J 7.05 Hz) and 1.24 (3H, t, J 7.1 Hz). m/z (ES⁺, 70V)462 (MH⁺).

EXAMPLE 21(S)-3-([4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(cis2.5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic

[0234] A solution of the compound of Example 19 (250 mg, 0.54 mmol) and2,5-dimethylpyrrolidine (cis/trans mixture 107 mg, 1.08 mmol) inmethanol (5 ml) was stirred at 40° for 2 days. The volatiles wereremoved in vacuo and the obtained residue chromatographed (silica; 2%MeOH/DCM) to afford the methyl ester of the title compound as a paleyellow foam (250 mg). This material was treated with LiOH.H₂O (30 mg) indioxan (3 ml) and water (4 ml) at room temperature for 1 h. A few dropsof AcOH were added and the volatiles were removed in vacuo. The residuewas chromatographed [silica; DCM (200), MeOH (20), AcOH (3), H₂O(2)] toafford an oil which was freeze-dried from aqueous methanol to afford thetitle compound as a pale yellow amorphous solid (140 mg). δH (DMSO-d⁶),9.69 (1H, s), 8.81 (1H, d, J 5.7 Hz), 8.14 (1H, d, J 5.8 Hz), 7.89 (1H,d, J 5.7 Hz), 7.58 (1H, d, J 9.0 Hz), 7.53 (1H, d, J 5.8 Hz), 7.37 (2H,d, J 8.6 Hz), 7.23 (2H, d, J 8.6 Hz), 5.10 (1H, m), 4.20 (2H, m), 3.32(1H, dd, J 13.9, 4.2 Hz), 3.11 (1H, dd, J 13.9, 11.8 Hz), 2.09 (2H, m),1.68 (2H, m) 1.27 (3H, d, J 6.4 Hz) and 1.21 (3H, d, J 6.3 Hz); m/z(ES⁺, 70V) 487 (MH⁺).

EXAMPLE 22 Ethyl(S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0235] A solution of the compound of Example 19 in EtOH (100 ml) wastreated with diethylamine (1.6 ml) and stirred at room temperature for16 h, concentrated in vacuo, then purified by chromatography (SiO₂;EtOAC/hexane;9-2:1) to give the title compound (2.84 g, 77%) as a whitesolid. δH (DMSO-d⁶, 350K), 9.69 (1H, s), 8.79 (1H, d, J 5.8 Hz), 8.13(1H, d, J 5.8 Hz), 7.84 (1H, dd, J 5.8,1.0 Hz), 7.50 (1H, dd, J 5.8, 0.7Hz), 7.35 (2H, d, J 8.6 Hz), 7.23 (2H, d, J 8.6 Hz), 5.22 (1H, dd, J9.8, 5.3 Hz), 4.20 (2H, qd, J 7.0, 1.0 Hz), 3.55 (4H, 1, J 7.1 Hz), 3.30(1H, dd, J 14.0, 5.3 Hz), 3.16 (1H, dd, J 14.1, 9.8 Hz), 1.24 (3H, t, J7.1 Hz) and 1.15 (6H, t, J 7.1 Hz). m/z (ES⁺, 70V) 489 (MH⁺).

EXAMPLE 23(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid

[0236] Prepared in a similar manner to the compound of Example 21 fromthe compound of Example 22 to give the title compound as a pale yellowamorphous solid. δH (DMSO-d⁶), 9.69 (1H, s), 8.80 (1H, d, J 5.7 Hz),8.14 (1H, d, J 5.8 Hz), 7.86 (1H, d, J 5.7 Hz), 7.52 (1H, d, J 5.8 Hz),7.42 (1H, d, J 9.0 Hz), 7.36 (2H, d, J 8.6 Hz), 7.24 (2H, d, J 8.6 Hz),5.17 (1H, m), 3.60-3.46 (4H, m), 3.32 (1H, dd, J 14.0, 4.6 Hz), 3.13(1H, dd, J 14.0, 10.1 Hz) and 1.15 (5H, t, J 7.1 Hz); m/z (ES⁺) 461(MH⁺).

EXAMPLE 24(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamnino)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0237] Prepared in a similar manner to the compound of Example 21 fromthe compound of Example 19 and dipropylamine to give the title compoundas a pale yellow amorphous solid. δH (DMSO-d⁶), 9.68 (1H, s), 8.80 (1H,d, J 5.7 Hz), 8.13 (1H, d, J 5.8 Hz), 7.86 (1H, d, J 5.7 Hz), 7.52 (1H,d, J 5.8 Hz), 7.36 (1H, masked d), 7.36 (2H, d, J 8.5 Hz), 7.23 (2H, d,J 8.5 Hz), 5.17 (1H, m), 3.58-3.39 (4H, m), 3.33 (1H, dd, J 14.0, 4.7Hz), 3.13 (1H, dd, J 14.0, 10.1 Hz), 1.63-1.48 (4H, m) and 0.85 (6H, t,J 7.3 Hz); m/z (ES⁺, 70V)489(MH⁺).

EXAMPLE 25 Ethyl(S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-[2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoate

[0238] Prepared in a manner similar to the compound of Example 21 fromthe compound of Example 20 and azepane to give the title compound as awhite solid. δH (DMSO-d⁶), 9.81 (1H, s), 8.94 (1H, d, J 5.7 Hz), 8.25(1H, d, J 5.7 Hz), 8.01 (1H, dd, J 5.7, 0.9 Hz), 7.66 (1H, d, J 5.7 Hz),7.44 (2H, d, J 8.6 Hz), 7.35 (2H, d, J 8.6 Hz), 5.32 (1H, dd, J 10.8,4.9 Hz), 4.30 (2H, q, J 7.0 Hz), 3.79 (4H, m), 3.43 (1H, dd, J 14.0, 4.9Hz), 3.22 (1H, dd, J 14.0, 10.8 Hz), 1.92 (4H, m), 1.61 (4H, m) and 1.35(3H, t, J 7.1 Hz). m/z (ES+. 70V) 515 (MH⁺).

EXAMPLE 26(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-1yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0239] A solution of the compound of Example 25 in THF (4 ml) and water(4 ml) was treated with lithium hydroxide (4 mg) and stirred at roomtemperature for 30min. The THF was removed and the solution acidified topH 2 with dilute hydrochloric acid solution and the precipitate isolatedby filtration to give the title compound (97 mg, 32%) as a pale yellowsolid. δH (DMSO-d⁶, 350K), 9.70 (1H, d, J 0.8 Hz), 8.81 (1H, d, J 5.8Hz), 8.16 (1H, d, J 5.8 Hz), 7.86 (1H, dd, J 5.8, 1.0 Hz), 7.52 (1H, dd,J 8.0, 0.8 Hz), 7.36 (2H, d, J 8.6 Hz), 7.24 (2H, d, J 8.6 Hz), 5.17(1H, m), 3.68 (4H, m), 3.33 (1H, dd, J 14.1, 10.0 Hz), 1.68 (4H, m) and1.54 (4H, m). m/z (ES⁺, 70V) 487 (MH⁺).

EXAMPLE 27 Ethyl(S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-[(2-[(2S),(5 S)-transdimethylpyrrolidin-1-yl]-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0240] To a solution of the compund of Example 19 (0.25 g, 0.56 mmol) inmethanol (3 ml) at room temperature was added(2S),(5S)-dimethylpyrrolidine trifluoroacetic acid salt (0.21 g, 1 mmol)and N,N-diisopropylethylamine (0.3 ml, 1.8 mmol). The mixture was heatedto 50°. After 6 h at 50° extra (2S),(5S)-dimethylpyrrolidinetrifluoroacetic acid salt (0.21 g, 1 mmol) and N,N-diisopropylethylamine(0.3 ml, 1.8 mmol) was added and the mixture heated to 70°. The reactionwas stirred at this temperature overnight before (2S),(5S)-dimethylpyrrolidine trifluoroacetic acid salt (0.21 g, 1 mmol) andN,N-diisopropylethylamine (0.3 ml, 1.8 mmol) was added. The mixture washeated at 70° for a further 24 h, partitioned between ethyl acetate (40ml) and water (30 ml). The organics were separated and washed withammonium chloride (2×30 ml), water (30 ml), brine (30 ml), dried(MgSO₄), and concentrated in vacuo. Column chromatography (SiO₂; 23:2;DCM:MeOH) gave the title compound as an off white foam (0.19 g, 63%). δH(CDCl₃), 8.68 (1H, br), 8.12 (1H, m), 7.45 (1H, d, J 5.7 Hz), 7.29-7.08(5H, m), 5.50 (2H, m), 3.85 (2H, d, J 7.1 Hz), 3.81 (3H, s), 3.37-3.30(2H, m), 2.18-2.05 (2H, m), 1.76-1.65 (2H, m), 1.41-1.15 (6H, m). m/z(ES⁺, 70V) 501 (MH⁺).

EXAMPLE 28 (S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-[(2S),(5S)-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]proanoic

[0241] To a solution of the compound of Example 13 (0.17 g, 0.34 mmol)in THF (3 ml) at room temperature was added a solution of LiOH.H₂O (23mg, 0.54 mmol) in water (1 ml). After 2 h the reaction mixture wasconcentrated in vacuo, redissolved in water (5 ml), acidified to pH 4with acetic acid. The resulting white precipitate was isolated byfiltration, washed with water. ether and dried in vacuo to give theproduct as an off white solid (80 mg, 47%) δH (DMSO-d6), 9.42 (1H, s ),8.78 (1H, dd, J 6.2, 1.9 Hz), 8.13 (2H, m), 7.67 (1H, dd, J 5.7, 0.7Hz), 7.37 (2H, m), 7.22 (2H, m), 5.12 (1H, m), 3.44-3.01 (4H, m), 2.16(2H, m), 1.72 (0.5H, m), 1.62 (1.5H, m), 1.31 (1H, d, J 6.5 Hz), 1.26(1H, d, J 6.4 Hz), 1.13 (2H, d, J 6.5 Hz) and 1.06 (2H, d, J 6.4 Hz).m/z (ES⁺, 70V) 487 (MH⁺).

EXAMPLE 29 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl1-2-[2-ethoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0242] A solution of Intermediate 11 (3.36 g, 9.6 mmol) and1,2-diethoxy-3,4-dioxocyclobut-1-ene (1.63 g, 9.6 mmol) in absoluteethanol (30 ml) was stirred at room temperature for 14 h. The volatileswere removed in vacuo affording a yellow foam. Chromatography (silica:50% EtOAc/Hexane-100% EtOAc) afforded the title compound as a yellowfoam (4.28 g, 94%). δH (CDCl₃) 9.29 (1H. s), 8.54 (1H. d, J 5.7 Hz),7.73 (2H, d, J 8.4 Hz), 7.43 (1H, masked br s), 7.42 (1H, d, J 5.7 Hz),7.12 (2H, d, J 8.4 Hz), 6.88 (1H, s), 6.54, 5.98 and 5.16 (together 1H,br s), 4.60 (1H. br s), 4.77 (2H, br m), 4.33 (2H, q, J 7.1 Hz),3.27-3.03 (2H, br m), 2.52 (3H, s), 1.43 (3H, t, J 7.1 Hz) and 1.32 (3H,t, J 7.2 Hz); m/z (ES⁺, 70V) 475 (MH⁺).

EXAMPLE 30 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-isopropoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0243] The title compound was prepared in a similar manner to Example29, from intermediate 11 and 1,2-diisopropoxy-3,4-dioxocyclobut-1-ene,and isolated as a light orange foam. δH (CDCl₃) 9.39 (1H, br s), 8.56(1H, d, J 5.7 Hz), 7.77 (1H, masked br s), 7.76 (2H, d, J 7.9 Hz), 7.41(1H, d, J 5.7 Hz), 7.11 (2H, d, J 8.4 Hz), 6.84 (1H, s), 6.36 and 5.18(togehter 1H, br s), 5.41-5.20 (1H, br m), 4.63 (1H, br s), 4.29 (2H, q,J 7.1 Hz), 3.27-3.06 (2H, br m), 2.49 (3H, s), 1.42 (6H, d, J 6.1 Hz)and 1.32 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 489 (MH⁺).

EXAMPLE 31 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[(2-(2-methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0244] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 23 and 2-methylpiperidine to give the titlecompound. δH (DMSO-d⁶); 9.75 (1H, s), 9.45 (1H, s), 8.56 (1H, d, J 5.5Hz), 7.86 (2H, m), 7.56 (1H, d, J 5.6 Hz), 7.21 (2H, m), 6.96 (1H, s),5.75 (1H, s), 5.18 (1H, m), 4.45 (1H, m), 4.18 (2H, m), 3.30-3.17 (3H,m), 3.02 (1H, dd, J 13.7, 10.1 Hz), 2.43 (3H, s), 1.78-1.32 (6H, m) and1.22-1.14 (6H, m); m/z (ES⁺, 70V) 528 (MH⁺).

EXAMPLE 32(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionicacid

[0245] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 31 to give the title compound as a yellow solid.δH (DMSO-d⁶), 9.77 (1H, s), 9.46 (1H, s), 8.58 (1H, d, J 5.6 Hz),7.90-7.78 (3H, m), 7.58 (1H, d, J 5.6 Hz), 7.25-7.22 (1H, m), 6.98 (1H,s), 5.14-5.08 (1H, m), 4.48 (1H, m), 4.05 (1H, m), 3.27-3.20 (2H, m),3.04-2.95 (1H, m), 2.46 (3H, s), 1.74-1.44 (6H, m) and 1.23 (3H, d, J6.8 Hz). m/z (ES⁺, 70V) 500 (MH⁺).

EXAMPLE 33 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0246] A solution of the compound of Example 30 (350 mg, 0.72 mmol) anddiethylamine (157 mg, 222 μl, 2.15 mmol) in absolute ethanol (10 ml) wasstirred at room temperature for 2 days. The volatiles were removed invacuo and the obtained orange foam was chromatographed (silica; EtOAc)affording the title compound as a light yellow foam (301 mg, 84%). δH(DMSO-d⁶, 350K) 9.61 (1H, s ), 9.14 (1H, s), 8.42 (1H, d, J 5.6 Hz),7.71 (2H, d, J 8.5 Hz), 7.39 (1H, d, J 5.6 Hz), 7.24 (1H, d, J 8.0 Hz),7.09 (2H, d, J 8.5 Hz), 6.81 (1H, s), 5.08 (1H, m), 4.06 (2H, q, J 7.1Hz), 3.41 (4H, q, J 7.1 Hz), 3.11 (1H, dd, J 14.1, 5.2 Hz), 2.96 (1H,dd, J 14.1, 9.7 Hz), 2.32 (3H, s ), 1.10 (3H, t, J 7.1 Hz) and 1.02 (6H,t, J 7.1 Hz); m/m/z (ES⁺, 70V) 502 (MH⁺).

EXAMPLE 34(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid

[0247] The compound of Example 33 (290 mg, 0.58 mmol) was treated withLiOH.H₂O (36 mg, 0.86 mmol) in dioxan (50 ml) and water (6 ml) at roomtemperatue for 1 h. A few drops of AcOH were added and the volatilesremoved in vacuo. The residue was chromatographed [silica; DCM(200-120), MeOH (20), AcOH (3), H₂O (2)] affording a yellow oil.Freeze-drying from aqueous methanol afforded the title compound as ayellow amorphous solid (226 mg, 82%). δH (DMSO-d⁶, 340K) 9,72 (1H, s),9.28 (1H, br s), 8.53 (1H, d, J 5.6 Hz), 7.82 (2H, d, J 8.5 Hz), 7.51(1H, d, J 5.6 Hz), 7.34 (1H, d, J 8.7 Hz), 7.21 (2H, d, J 8.5 Hz), 6.92(1H, s ), 5.11 (1H, m), 4.60-4.41 (4H, m), 3.23 (1H, dd, J 14.0,4.6 Hz),3.04 (1H, dd, J 14.0, 10.1 Hz), 2.43 (3H, s), 1.12 (6H, t, J 7.1 Hz);m/z (ES⁺, 70V) 474 (MH⁺).

EXAMPLE 35 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0248] Prepared in a similar manner to the compound of Example 33 fromthe compound of Example 30 and di-n-propylamine to give the titlecompound as a light yellow foam. δH (DMSO-d⁶, 350K) 9.74 (₁s ), 9.27(1H, s), 8.55 (1H, d, J 5.6 Hz), 7.85 (2H, d, J 8.5 Hz), 7.52 (1H, d, J5.6 Hz), 7.31 (1H, d, J 8.7 Hz), 7.21 (2H, d, J 8.5 Hz), 6.94 (1H, s),5.19 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.46 (4H,.m), 3.25 (1H, dd, J14.1, 5.1 Hz), 3.09 (1H, dd, J 14.1, 9.7 Hz), 2.45 (3H, s), 1.54 (4H,m), 1.23 (3H, t, J 7.1 Hz) and 0.86 (6H, t, J 7.1 Hz); m/z (ES⁺, 70V)530 (MH⁺).

EXAMPLE 36(S)-3-[4-(3-Methyl-21-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid

[0249] Prepared in a similar manner to the compound of Example 34 fromthe compound of Example 35 to give the title compound as a yellowamorphous solid. δH (DMSO-d⁶, 340K) 9.74 (1H, s), 9.32 (1H, br s), 8.54(1H, d, J 5.7 Hz), 7.83 (2H, d, J 8.5 Hz), 7.52 (1H, d, J 5.7 Hz), 7.30(1H, d, J 9.0 Hz), 7.21 (2H, d, J 8.5 Hz), 6.94 (1H, s), 5.13 (1H, m),3.53-3.43 (2H, m), 3.42-3.31 (2H, m), 3.24 (1H, dd, J 14.1, 4.6 Hz),3.04 (1H, dd, J 14.1, 10.1 Hz), 2.43 (3H, s ), 1.57-1.46 (m) and 0.83(6H, t, J 7.3 Hz); m/z (ES⁺, 70V) 502 (MH⁺).

EXAMPLE 37 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(cis2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0250] Prepared in a similar manner to the compound of Example 33, fromthe compound of Example 30 and cis 2,5-dimethylpyrrolidine. δH(DMSO-d⁶), 9.75 (1H, s), 9.45 (1H, s), 8.56 (1H, d, J 5.6 Hz), 7.84 (2H,m), 7.65 (1H, d, J 9.1 Hz), 7.55 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.5Hz), 6.96 (1H, s ), 5.13 (1H, m), 4.22-4.13 (4H, m), 3.22 (1H, dd, J13.9, 4.6 Hz), 3.04 (1H, dd, J 13.8, 10.6 (Hz), 2.43 (3H, s), 2.12-2.05(2H, m), 1.70-1.64 (2H, m), 1.24-1.15 (9H, m); m/z (ES⁺, 70V) 528 (MH⁺).

EXAMPLE 38 (S)-3-[4-(3-Methyl-2,7-naphthyridin-1 lamino)phenyl]-2-[2-(cis2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0251] Prepared in a similar manner to the compound of Example 34 fromthe compound of Example 37 to give the title compound as a yellowamorphous solid. δH (DMSO-d⁶, 340K) 9.72 (1H, s), 9.28 (1H, br s), 8.54(1H, d, J 5.6 Hz), 7.82 (2H, d, J 8.5 Hz), 7.51 (1H, d, J 5.6 Hz), 7.22(2H, d, J 8.5 Hz), 7.16 (1H, d, J 9.0 Hz), 6.92 (1H, s), 5.08 (1H, m),4.19 (1H, m), 3.23 (1H, dd, J 14.1, 4.7 Hz), 3.07 (1H, dd, J 14.1, 9.7Hz), 2.42 (3H, s), 2.15-2.03 (2H, m), 1.73-1.62 (2H, m), 1.25 (3H, d, J6.4 Hz) and 1.22 (3H, d, J 6.4 Hz); m/z (ES⁺, 70V) 500 (MH⁺).

EXAMPLE 39 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0252] A solution of the compound of Example 29 (392 mg, 0.83 mmol) andazepane (164 mg, 1.66 mmol) in absolute ethanol (4 ml) was stirred atroom temperature for 0.5 h. The volatiles were removed in vacuo and theobtained yellow foam chromatographed (silica; 1-2% EtOH/DCM) to affordthe title compound as a yellow powder (362 mg, 83%). δH (DMSO-d⁶, 350K)9.76 (1H, s), 9.29 (1H, s), 8.58 (1H, d, J 5.6 Hz), 7.88 (2H, d, J 8.6Hz), 7.55 (1H, d, J 5.6 Hz), 7.43 (1H, br s), 7.23 (2H, d, J 8.6 Hz),6.97 (1H, s), 5.22 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.68 (4H, m), 3.26(1H, dd, J 14.1, 5.1 Hz), 3.10 (1H, dd, J 14.1, 9.8 Hz), 2.47 (3H, s),1.70-1.65 (1H, m), 1.57-1.51 (4H, m) and 1.25 (3H, t, J 7.1 Hz); m/z(ES⁺, 70V) 528 (MH⁺).

EXAMPLE 40 (S)-3-14-(3-Methyl -2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0253] The compound of Example 39 (350 mg, 0.66 mmol) was treated with asolution of LiOH.H₂O (41 mg, 0.98 mmol) in dioxan (3 ml) and water (4ml) for 1 h. A few drops of AcOH were added and the volatiles removed invacuo. The residue was treated with water and the yellow solid collectedby filtration with water washing, and dried to give the title compoundas a yellow powder (278 mg, 84%). δH (DMSO-d⁶, 350K) 9.75 (1H, s), 9.29(1H, br s), 8.57 (1H, d, J 5.6 Hz), 7.87 (2H, d, J 8.5 Hz), 7.54 (1H, d,J 5.6 Hz), 7.34 (1H, d, J 9.0 Hz), 7.24 (1H, d, J 8.5 Hz), 6.96 (1H, s), 5.16 (1H, m), 3.70-3.60 (4H, m), 3.27 (1H, dd, J 14.0, 4.7 Hz), 3.08(1H, dd, J 14.0, 10.0 Hz), 2.47 (3H, s), 1.78-1.65 (4H, m) and 1.60-1.49(4H, m); m/z (ES⁺, 70V) 500 (MH⁺).

EXAMPLE 41 Methyl(S)-3[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-isopropoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0254] N,N-DIPEA (1.96 g, 2.4 ml, 15.2 mmol) was added to a stirredsuspension of Intermediate 13 (2.0 g, 34.90 mmol) and1,2-diisopropoxy-3,4-dioxocyclobut-1-ene (1.03 g, 5.20 mmol) in absoluteethanol (30 ml). The reaction mixture was stirred at room temperaturefor 18 h, then the volatiles were removed in vacuo. The residue waspartitioned between EtOAc and water. The phases were separated and theaqueous layer re-extracted with EtOAc. The combined organic extractswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresidue was chromatographed (silica: 50% EtOAc/Hexane -100% EtOAc)affording the title compound as a white foam (1.93 g, 83%). δH (CDCl₃)9.73 (1H, s), 8.67 (1H, d, J 6.0 Hz), 7.63 (1H, d, 6.0 Hz), 7.28-7.20(4H, m), 7.18 (1H, s), 6.49 and 5.94 (togher 1H, br s), 5.39 (1H, m),5.22 and 4.69 (together 1H, br s), 3.83 (3H, s), 3.35-3.15 (2H, br m),2.51 (3H, s), 1.45-1.41 (6H, overlapping d); m/z (ES⁺, 70V) 476 (MH⁺).

EXAMPLE 42 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-ethoxy-3,4-dioxocyclobut-1-enylamino]-propanoate

[0255] A solution of Intermediate 15 (10.9 g, 31.0 mmol) and1,2-diethoxy-3,4-dioxocyclobut-1-ene (5.54 g, 32.6 mmol) in absoluteethanol (100 ml) was stirred at room temperature for 3.5 h. Theresulting precipitate was isolated by filtration, washed with Et₂O,affording a very slighly yellow amorphous solid (10.6 g). Chromatography(silica; 75% EtOAc/Hexane -100% EtOAc) afforded the title compound as awhite solid (8.44 g, 57%). δH (CDCl₃) 9.46 (1H, s), 9.12 and 8.94(together 1H, d, J 8.1 Hz), 8.59 (1H, d, J 5.7 Hz), 7.62 (1H, d, J 5.7Hz), 7.22 (1H, s), 7.21 (2H, d, J 8.6 Hz), 7.11 (2H, d, J 8.6 Hz), 4.78and 4.39 (together 1H, m), 4.57-4.38 (2H, m), 4.11-3.98 (2H, m), 3.26(1H, dd, J 14.0, 7.0 Hz), 3.14 (1H, dd, J 14.0, 10.0 Hz), 2.28 (3H, s),1.26-1.15 (3H, m) and 1.15-1.01 (3H, m); m/z (ES⁺, 70V) 476 (MH⁺).

EXAMPLE 43 Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0256] A solution of the compound of Example 41 (350 mg, 0.74 mmol) anddiethylamine (134 mg, 1.83 mmol) in methanol (10 ml) was stirred at roomtemperature for 3 days. The volatiles were removed in vacuo and theresidue chromatographed (silica; 5% DCM: 95% EtOAc) to afford the titlecompound as a white foam (298 mg, 83%). δH (CDCl₃) 9.70 (1H, s), 8.69(1H, d, J 5.9 Hz), 7.55 (1H, d, J 5.9 Hz), 7.24 (2H, d, J 8.6 Hz), 7.18(2H, d, J 8.6 Hz), 7.14 (1H, s), 5.48 (1H, m), 3.83 (3H, s), 3.70-3.30(4H, br s), 3.35 (1H, dd, J 14.2, 4.8 Hz), 3.30 (1H, dd, J 14.2, 5.7Hz), 2.45 (3H, s) and 1.25 (6H, t, J 7.2 Hz); m/z (ES⁺, 70V) 489 (MH⁺).

EXAMPLE 44(S)-3-[4-(3-Methyl-2,7-naphthyridin-1yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0257] The compound of Example 43 (285 mg, 0.58 mmol) was treated with asolution of LiOH.H₂O (36 mg, 0.86 mmol) in dioxan (5 ml) and water (7ml) at room temperature for 1.5 h. A few drops of AcOH were added andthe volatiles were removed in vacuo. The residue was chromatographed[silica; DCM (200), MeOH (20), AcOH (3), H₂O (2)] to afford an oil.Freeze-drying from aqueous methanol afforded the title compound as avery pale yellow amorphous solid (230 mg, 83%). δH (DMSO-d⁶) 9.60 (1H,s), 8.73 (1H, d, J 5.7 Hz), 7.76 (1H. d, J 5.7 Hz), 7.75 (1H, masked d),7.35 (2H, d, J 8.5 Hz), 7.34 (1H, s), 7.23 (2H, d, J 8.5 Hz), 5.16 (1H,m), 3.70-3.35 (4H, br m), 3.32 (1H, dd, J 13.0, 3.9 Hz), 3.07 (1H, dd, J13.9, 11.3 Hz), 2.36 (3H, s) and 1.11 (6H, t, J 7.0 Hz); m/ (ES⁺, 70V)475 (MH⁺).

EXAMPLE 45 Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,Ndi-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0258] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and di-n-propylamine to give the titlecompound as a very pale yellow foam. δH (CDCl₃) 9.69 (1H, s ), 8.69 (1H,d, J 5.8 Hz), 7.53 (1H, d, J 5.8 Hz), 7.23 (2H, d, J 8.6 Hz), 7.17 (2H,d, J 8.6 Hz), 5.48-5.42 (1H, m), 5.39-5.36 (1H, m), 3.84 (3H, s),3.80-3.40 (2H, br s), 3.38-3.29 (2H, m), 3.40-3.00 (2H, br s), 2.45 (3H,s ), 1.69-1.58 (4H, m) and 0.90 (6H, t, J 7.3 Hz); m/z (ES⁺, 70V) 517(MH⁺).

EXAMPLE 46(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0259] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 45 to give the title compound as a very paleyellow amorphous solid. δH (DMSO-d⁶, 350K) 9.58 (1H, s), 8.71 (1H, d, J5.7 Hz), 7.71 (1H, d, J 5.7 Hz), 7.34 (2H, d, J 8.6 Hz), 7.33 (1H, s),7.30 (1H, d, J 9.0 Hz), 7.23 (2H, d, J 8.6 Hz), 5.17 (1H, m), 3.54-3.47(2H, m), 3.45-3.37 (2H, m), 3.32 (1H, dd, J 14.1, 4.7 Hz), 3.13 (1H, dd,J 14.1, 11.0 Hz), 2.40 (3H, s), 1.59-1.49 (4H, m) and 0.85 (6H, t, J 7.4Hz); m/z (ES⁺, 70V) 503 (MH⁺).

EXAMPLE 47 Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0260] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and cis-2,5-dimethylpyrrolidine to give thetitle compound as a white foam. δH (CDCl₃) 9.72 (1H, s), 8.68 (1H, d, J5.8 Hz), 7.58 (1H, d, J 5.8 hz), 7.23 (2H, d, J 8.6 Hz), 7.19 (2H, d, J8.6 Hz), 7.16 (1H, s), 5.47-5.43 (1H, m), 5.40-5.38 (1H, m), 4.30-4.10(2H, br s), 3.83 (3H, s), 3.38-3.28 (2H, m), 2.47 (3H, s), 2.18-2.10(2H, m), 1.77-1.71 (2H, m), 1.39 (3H, d, J 6.5 Hz) and 1.33 (H, d, J 6.5Hz); m/z (ES⁺, 70V) 515 (MH⁺).

EXAMPLE 48(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2.5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0261] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 47 to give the title compound as a pale yellowamorphous solid. δH (DMSO-d⁶, 350K) 9.59 (1H, s), 8.71 (1H, d, J 5.7Hz), 7.72 (1H, d, J 5.7 Hz), 7.36 (2H, d, J 8.6 Hz), 7.34 (1H, s), 7.25(2H, d, J 8.6 Hz), 7.17 (1H, d, J 8.8 Hz), 5.16 (1H, m), 4.24-4.19 (2H,m), 3.33 (1H, dd, J 14.1, 4.8 Hz), 3.16 (1H, dd, J 14.1, 9.8 Hz), 2.40(3H, s), 2.17-2.05 (2H, m), 1.76-1.65 (2H, m), 1.29 (3H, d, J 6.4 Hz)and 1.24 (3H, d, J 6.4 Hz); m/z (ES⁺, 70V) 501 (MH⁺).

EXAMPLE 49 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0262] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 42 and azepane to give the title compound as awhite powder. δH (DMSO-d⁶, 350K) 9.61 (1H, s), 8.73 (1H, d, J 5.7 Hz),7.74 (1H, d, J 5.7 Hz), 7.48 (1H, d, J 8.0 Hz), 7.36 (2H, d, J 8.5 Hz),7.35 (1H, s), 7.26 (2H, d, J 8.5 Hz), 5.25 (1H, m), 4.21 (2H, q, J 7.1Hz), 3.71-3.67 (4H, m), 3.33 (1H, dd, J 14.1, 5.3 Hz), 3.17 (1H, dd, J14.1, 9.8 Hz), 2.42 (3H, s), 1.74-1.66 (4H, m), 1.58-1.51 (4H, m) and1.25 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V) 529 (MH⁺).

EXAMPLE 50a Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)3,4-dioxocyclobut-1-enylamino]propanoate

[0263] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and azepane to give the title compound as awhite foam. δH (DMSO-d⁶), 9.59 (1H, s), 8.73 (1H. d, J 5.7 Hz), 7.87(1H, m), 7.77 (1H, d, J 5.7 Hz), 7.30 (1H, m), 7.30 (2H, d, J 8.6Hz),7.24 (2H, d, J 8.5 Hz), 5.21 (1H, m), 3.72 (3H, s), 3.80-3.45 (4H, m),3.39-3.30 (1H, m), 3.15-3.05 (1H, m), 2.50 (3H, s) and 1.70-1.44 (8H,m). m/z (ES⁺, 70V) 515 (MH⁺).

EXAMPLE 50b Isopropyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0264] The compound of Example 51 (641 mg, 1.28 mmol) was dissolved withheating in isopropyl alcohol (80 ml). To the solution at ambienttemperature was added HOBt (199 mg, 1.47 mmol), and once dissolved EDC(282 mg, 1.47 mmol) was added. After 10min the now cloudy solution washeated briefly to give a clear solution which was stirred at ambienttemperature for 5 h. The solvent was removed, the residue taken up intoDCM, washed (NaHCO₃ solution), dried (MgSO₄), concentrated in vacuo andthe resulting residue purified by chromatography (SiO₂; EtOAc) to givethe title compound as a white solid (592 mg 85%). δH (DMSO) 9.60 (1H,s), 8.73 (1H, d, J 5.8 Hz), 7.77 (2H, m), 7.35 (3H, m), 7.25 (2H, d, J6.7 Hz), 5.17 (1H, m), 4.97 (1H, sept, J 6.2 Hz), 3.65 (4H, br), 3.27(1H, dd), 3.12 (1H, dd, J 13.8, 10.5 Hz), 2.37 (3H, s), 1.64 (4H, br s),1.49 (4H, br s), 1.23 (3H, d, J 6.3 Hz), 1.21 (3H, d, J 6.3 Hz); m/z(ES⁺, 70V) 543 (MH⁺).

EXAMPLE 50c Benzyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0265] Prepared in a similar manner to the compound of Example 50b frombenzylalcohol. δH (DMSO) 9.71 (1H, s ), 8.83 (1H, d, J 5.7 Hz), 7.85(1H, d, J 5.8 Hz), 7.59 (1H, d), 7.50-7.40 (8H, m), 7.36 (2H, d, J 6.6Hz), 5.45 (1H, m), 5.34 (2H, s), 3.78 (4H, t, J 6.0 Hz), 3.47 (1H, dd, J14.1, 5.2 Hz), 3.30 (1H, dd, J 14.1, 9.9 Hz), 2.52 (3H, s), 1.77 (4H,br), 1.63 (4H, br). m/z (ES⁺, 70V) 590 (MH⁺).

EXAMPLE 50d n-Pentyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl)-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0266] Prepared in a similar manner to the compound of Example 50b fromn-pentylalcohol. δH (CDCl₃, 400 MHz) 9.67 (1H, s), 8.69(1H, d, J 5.8Hz), 7.55 (1H, dd, J 5.8, 0.8 Hz), 7.22 (4H, m), 7.13 (1H, s), 5.67 (1H,d, J 8.6 Hz), 5.47 (1H, m), 4.17 (2H, q, J 6.8 Hz), 3.88 (2H, br), 3.46(2H, br), 3.32 (2H, d, J 6.0 Hz), 2.46 (3H, s), 1.76 (4H, br), 1.68 (2H,t, J 7.0 Hz), 1.61 (4H, br), 1.34 (4H, m), 0.92 (3H, t, J 6.1 Hz).

EXAMPLE 50e n-Butyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0267] Prepared in a similar manner to the compound of Example 50b fromn-butanol. δH (d⁶ DMSO) 9.61 (1H, s), 8.71 (1H, d, J 8.2 Hz), 7.74 (1H,d, J 8.2 Hz), 7.41 (3H, m), 7.29 (2H, d, J 8.54 Hz), 5.26 (1H, m), 4.16(2H, m), 3.69 (4H, m), 3.35 (1H, dd, J 12.0, 5.9 Hz), 3.18 (1H, dd, J11.1, 5.8 Hz), 2.43 (3H, s), 1.71 (4H, br), 1.66 (2H, m), 1.57 (4H, m),1.37 (2H, m), 0.94 (3H, t); m/z (ES⁺, 70V) 557 (MH⁺).

EXAMPLE 50f Cyclopentyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0268] Prepared in a similar manner to the compound of Example 50b fromcyclopentanol. δH (d⁶ DMSO) 9.60 (1H, s), 8.72 (1H, d, J 8.1 Hz), 7.74(1H, d, J 8.1 Hz), 7.35 (3H, m), 7.26 (2H, d, J 8.5 Hz), 5.20 (1H, m),3.69 (4H, m), 3.28 (1H, dd, J 12.0, 5.8HZ), 3.14 (1H, dd, J 11.0, 5.7Hz), 2.42 (3H, s), 1.87 (2H, m), 1.70-1.57 (17H, br m); m/z (ES⁺, 70V)569 (MH⁺).

EXAMPLE 50g N,N-Dimethylaminoethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0269] To a solution of the compound of Example 51 (700 mg, 1.40 mmol)and N,N-dimethylethanolamine (374 mg, 4.20 mmol) in DCM (5 ml) was addedPyBOP (873 mg, 1.68 mmol). The solution was left at room temperatureovernight and the solvent removed under high vacuum. The rsidue wastaken up in DCM (50 ml), washed with saturated NaHCO₃ (3×50 ml),extracted into 0.1M HCl (3×50 ml) and the aqueous soution rebasified(NaHCO₃). The product was then extracted into DCM (3×50 ml), dried(MgSO₄) and concentrated in vacuo to give the title compound as an offwhite solid (452 mg). δH (DMSO) 9.70 (1H, s), 8.81 (1H, d, J 5.7 Hz),7.82 (1H, d, J 5.8 Hz), 7.50-7.40 (4H, m), 7.37 (2H, d, J 8.6 Hz), 5.36(1H, m), 4.33 (2H, m), 3.78 (4H, m), 3.43 (1H, dd, J 14.2, 5.2 Hz), 3.28(1H, dd, J 14.2, 9.7 Hz), 2.66 (2H, m), 2.52 (3H, s), 2.33 (6H, s), 1.79(4H, br m), 1.65 (4H, br m); m/z (ES⁺, 70V) 572 (MH⁺).

EXAMPLE 50h Morpholino-N-ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)-phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0270] Prepared in a similar manner to the compound of Example 50 g from4-(2-hydroxyethyl)morpholine. δH (DMSO) 9.61 (1H, s), 8.73 (1H, d, J5.7HZ), 7.74 (1H, d, J 5.7 Hz), 7.44 (1H, d, J 9.3 Hz), 7.36 (3H, m),7.28 (2H, d, J 8.6 Hz), 5.27 (1H, m), 4.27 (2H, m), 3.69 (4H, t, l 6.0Hz), 3.58 (4H, m), 3.34 (1H, dd, J 14.2, 5.2 Hz), 3.18 (1H, dd, J 14.2,9.7 Hz), 2.62 (2H, t, J 5.7 Hz), 2.45 (7H, m), 1.69 (4H, m), 1.56 (4H,br m); m/z (ES⁺, 70V), 614 (MH⁺).

EXAMPLE 51(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0271] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 50a to give the title compound as a pale yellowpowder. δH (DMSO-d⁶, 350K) 9.58 (1H, s), 8.70 (1H, d, J 5.7 Hz), 7.71(1H, d, J 5.7 Hz), 7.34 (2H, d, J 8.6 Hz), 7.33 (1H, masked s), 7.26(1H, masked s), 7.25 (2H, d, J 8.6 Hz), 5.17 (1H, m), 3.70-3.60 (4H, m),3.32 (1H, dd, J 14.1, 4.8 Hz), 3.14 (1H, dd, J 14.1, 9.9 Hz), 2.41 (3H,s), 1.74-1.60 (4H, m) and 1.57-1.49 (4H, m); m/z (ES⁺, 70V) 501 (MH⁺).

EXAMPLE 52Methyl-(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[(2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0272] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and trans 2,5-dimethylpyrrolidine to give thetitle compound. δH (DMSO-d⁶) 9.45 (1H, s), 8.59 (1H, d, J 5.7 Hz), 7.62(2H, m), 7.20 (3H, m), 7.10 (2H, m), 5.10 (1H, m), 4.18 (2H, m), 3.57(3H, s), 3.15-2.85 (2H, m), 2.23 (3H, s), 2.05 (2H, m), 1.45 (2H, m),0.75 (6H, m). m/z (ES⁺, 70V) 514 (MH⁺).

EXAMPLE 53(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl-2-[2-(trans-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionicacid

[0273] Prepared in a similar fashion to the compound of Example 44 fromthe compound of Example 52 to give the title compound as a white solid.δH (DMSO-d^(6,) 350K), 9.58 (1H, s), (8.70 (1H, d, J 5.7 Hz), 7.71 (1H,d, J 5.7 Hz), 7.37-7.21 (6H, m), 5.14 (1H, m), 4.37 (2H, d, J 6.74Hz),0.4×3.35 (1H, dd, J 14.1, 4.5 Hz), 0.6×3.32 (1H, dd, J 14.2, 5.1 Hz),0.6×3.20 (1H, dd, J 14.1, 9.7 Hz), 0.4×3.11 (1H, dd, J 14.1, 9.5 Hz),2.38 (3H, s), 2.17 (2H, m), 1.62 (2H, m), 1.11 (3H, 0.6, d, J 6.47 Hz),1.04 (3H, x 0.4, d, J 6.4 Hz). m/z (ES⁺, 70V) 501 (MH⁺).

EXAMPLE 54 Methyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(2-methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0274] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and 2-methylpiperidine to give the titlecompound as an off white foam. δH (DMSO-d⁶), 9.75 (1H, s), 8.88 (1H, d,J 5.7 Hz), 8.18-8.07 (1H, m), 7.92 (1H, d, J 5.75 Hz), 7.5-7.32 (5H, m),5.38 (1H, m), 4.6 (1H, m), 4.18 (1H, m), 3.88 (3H, s), 3.56-3.14 (3H,m), 2.64 (3H, s), 1.95-1.50 (6H, m) and 1.30-1.24 (3H, m). m/z (ES⁺,70V) 515 (MH⁺).

EXAMPLE 55(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(2-methylpiperidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionicacid

[0275] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 54 to give the title compound as a white solid.δH (DMSO-d⁶, 350K), 9.59 (1H, s ), 8.70 (1H, d, J 5.7 Hz), 7.71 (1H, d,J 5.7 Hz), 7.46 (1H, m), 7.35-7.33 (3H, m), 7.26-7.23 (2H, m), 5.16 (1H,m), 4.47 (1H, m), 4.04 (1H, m), 3.20 (1H, dd, J 14.2, 4.6 Hz), 3.10 (1H,dd, J 14.1, 9.8 Hz), 2.39 (3H, s), 1.80-1.40 (6H, m), 1.24 and 1.21(together 3H, d, J 6.8 Hz); m/z (ES⁺, 70V) 501 (MH⁺).

EXAMPLE 56Methyl-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-diisobutylamino)-3,4-dioxocyclobut-1-enylamino]propanoate

[0276] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 41 and diisobutylamine to give the titlecompound as a white foam. δH (DMSO-d⁶), 9.58 (1H, s), 8.73 (1H, d, J 5.7Hz), 7.76 (2H, d, J 5.8 Hz), 7.39-7.30 (3H, m), 7.20 (2H, d, J 8.5 Hz),5.3 (1H, m), 3.72 (3H, s), 3.40-3.00 (4H, m), 2.35 (3H, s); 1.88-1.70(12H, m). m/z (ES⁺, 70V) 545 (MH⁺).

EXAMPLE 57(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-1yloxy)phenyl]-2-[2(N,N-diisobutylamino)-3,4-dioxocyclobut-1-enylamino]propionicacid

[0277] Prepared in a similar manner to the compound of Example 44 fromthe compund of Example 56 to give the title compound as a white solid.δH (DMSO-d⁶, 350K), 9.58 (1H, s), 8.70 (1H, s), 7.72 (1H, d, J 5.7 Hz),7.33 (1H, m), 7.35-7.26 (3H, m), 7.22 (2H, d, J 8.6 Hz), 5.18 (1H, m),3.41-3.08 (4H, m), 2.40 (3H, s), 1.91-1.80 (4H, m), 0.85 (6H, d, J 6.6Hz) and 0.83 (6H, d, J 6.6 Hz); m/z (ES⁺, 70V) 531 (MH⁺).

EXAMPLE 58 Ethyl (S)-3-[4-(3-ethyl-2,7-naphthyridin-1-ylamino)phenyl]-2-(2-azepan-1-yl)3,4-dioxocyclobut-1-enylamino]propanoate

[0278] Prepared in a similar manner to the compound of Example 3 to givethe title compound as a yellow foam. δH (DMSO-d⁶), 9.74 (1H, s), 9.45(1H, s), 8.55 (1H, d, J 5.6 Hz), 7.86 (2H, d, J 8.5 Hz), 7.79 (1H, d, J9.0 Hz), 7.57 (1H, d, J 5.6 Hz), 7.19 (2H, d, J 8.3 Hz), 6.95 (1H, s ),5.14 (1H, nr, m), 4.15 (2H, q, J 6.8 Hz), 3.66-3.44 (4H, m), 3.22 (1H,dd, J 13.5, 9.0 Hz), 3.00 (1H, dd, J 13.8, 10.8 Hz), 2,70 (2H, q, J 7.5Hz), 1.59-1.44 (8H, m), 1.28-1.12 (6H, m). m/z (ES⁺, 70V) 542 (MH⁺).

EXAMPLE 59(S)-3-[4-(3-Ethyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl])-3,4-dioxocyclobut-1-enylamino]propionicacid

[0279] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 58 to give the title compound as a yellow solid.δH (DMSO-d⁶, 360K), 9.64 (1H, s), 9.13 (1H, s), 8.46 (1H, d, J 5.6 Hz);7.76 (2H, d, J 8.5 Hz), 7.45 (1H, d, J 5.6 Hz), 7.11 (3H, m), 6.84 (1H,s), 5.0 (1H, m), 3.55 (4H, m), 3.15 (1H, dd, J 14.1, 4.8 Hz), 2.98 (1H,dd, J 14.1, 9.3 Hz), 2.65 (2H, q, J 7.5 Hz), 1.64-1.37 (8H, m) and 1.20(3H, t, J 7.5 Hz). m/z (ES⁺, 70V) 514 (MH⁺).

EXAMPLE 60(S)-3-[4-(3-Ethyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[(2-(,cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoicacid

[0280] Prepared in a similar manner to the compound of Example 4 to givethe title compound as a yellow solid. δH (DMSO-d⁶, 350K) 9.76 (1H, s),9.29 (1H, s), 8.58 (1H, d, J 5.6 Hz), 7.87 (2H, d, J 6.3 Hz), 7.57 (1H,d, J 5.6 Hz), 7.24 (2H, d, J 8.6 Hz), 7.11 (1H, m), 6.96 (1H, s), 5.09(1H, m), 4.22 (2H, m), 3.26 (1H, dd, J 14.1, 4.7 Hz), 3.12 (1H, dd, J14.1, 9.3 Hz), 2.76 (2H, q, J 7.5 Hz), 2.12 (2H, m), 1.7 (2H, m) and1.25 (6H, m); m/z (ES⁺, 70V) 514 (MH⁺).

[0281] The following compounds were prepared in a similar manner to thecompound of Example 40.

EXAMPLE 61(S)-3-[4-(3-Ethyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0282] δH (DMSO-d⁶) 9.82 (1H, s), 9.51 (1H, s), 8.63 (1H, d, J 5.6Hz),7.91 (2H, d, J 8.5 Hz), 7.74 (1H, d, J 9.1 Hz), 7.65 (1H, d, J 5.6 Hz),7.28 (2H, d, J 8.5 Hz), 7.02 (1H, s), 5.14 (1H, m), 3.68-3.50 (4H, m),3.28 (1H, dd, J 14.0, 4.1 Hz), 3.06 (1H, dd, J 13.8,11.9 Hz), 2.77 (2H,q, J 7.5 Hz), 1.33 (3H, t, J 7.5 Hz) and 1.66 (6H, t, J 7.1 Hz); m/z(ES⁺, 70V) 488 (MH⁺).

EXAMPLE 62(S)-3-[4-(3-Ethyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid

[0283] δH (DMSO-d⁶, 360K) 9.59 (1H, s), 8.70 (1H, d, J 5.7 Hz), 7.74(1H, d, J 5.7 Hz), 7.38-7.23 (5H, m), 5.20(1H, m), 3.60-3.50 (4H, m),3.32 (1H, dd, J 14.2,4.7 Hz), 3.15 (1H, dd, J 14.1, 10.0 Hz), 2.68 (2H,q, J 7.5 Hz), 1.19-1.13 (9H, m); m/z (ES⁺, 70V) 489 (MH⁺).

EXAMPLE 63(S)-3-[4-(3-Ethyl-2,7-naphthrydin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0284] δH (DMSO-d⁶, 360K) 9.59 (1H, s), 8.70 (1H, d, J 5.7 Hz), 7.74(1H, d, J 5.8 Hz), 7.38-7.25 (5H, m), 5.20 (1H, m), 3.68 (4H, m), 3.32(1H, dd, J 14.2, 4.8 Hz), 3.14 (1H, dd, J 14.2, 9.9 Hz), 2.69 (2H, q, J7.5 Hz), 1.72-1.50 (8H, m) and 1.18 (3H, t, J 7.5 Hz); m/z (ES⁺, 70V),515 (MH⁺).

EXAMPLE 64(S)-3-[4-(3-Ethyl-2,7-naphthyridin-1yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0285] δH (CDCl₃) (DMSO-d⁶, 360K) 9.59 (1H, s), 8.70 (1H, d, J 5.7 Hz).7.74 (1H, d, J 5.7 Hz), 7.38-7.21 (5H, m), 7.05 (1H, m), 5.12 (1H, m),4.2 (2H, m), 3.33 (1H, dd, J 14.2, 4.8 Hz), 3.17 (1H, dd, J 14.2, 9.6Hz), 2.69 (2H, q, J 7.5 Hz), 2.15 (2H, m), 1.7 (2H, m), 1.3-1.13 (9H,m); m/z (ES⁺, 70V) 515 (MH⁺).

EXAMPLE 65Methyl-(S)-3-{(4-(3-methoxycarbonyl)-2,7-naphthyridin-1-ylamino)phenyl}-2-[(2-isopropoxy-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0286] Prepared in a similar manner to the compound of Example 1 fromthe intermediate 5 to give the title compound. δH (CD₃OD) 9.7 (1H, s),8.57 (1H, d, J 5.6 Hz), 8.57 (2H, br), 7.79 (1H, s), 7.73 (1H, d), 7.15(2H, d), 5.20 (1H, m), 5.05 and 4.62 (1H, 2 x br), 3.92 (3H, s), 3.79((3H, s), 3.27 (1H, dd), 2.96 (1H, dd), 1.36 (6H, d, J 6.2 Hz); m/z(ES⁺, 70V) 519 (MH⁺).

EXAMPLE 66Methyl-(S)-3-{(4-(3-methoxycarbonyl)-2,7-naphthyridin-1-ylamino)phenyl}-3-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoate

[0287] Prepared in a similar manner to the compound of Example 3 fromthe compound of Example 65 and diethylamine to give the title compound.δH (CD₃OD) 9.66 (1H, s), 8.61 (1H, d, J 5.7 Hz), 7.94 (1H, d, J 8.6 Hz),7.78 (1H, s), 7.72 (1H, d, J 5.7 Hz), 7.21 (2H, d, J 8.6 Hz), 5.35 (1H,m), 3.93 (3H, s), 3.80 (3H, s), 3.56 (4H, br), 3.32 (1H, dd), 3.04 (1H,dd), 1.18 (6H, t, J 7.1 Hz); m/z (ES⁺, 70V) 532 (MH⁺).

EXAMPLE 67(S)-3-{(4-(3-Methoxycarbonyl)-2,7-naphthyridin-1-ylamino)phenyl}-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoicacid

[0288] Prepared in a similar manner to the compound of Example 4 fromthe compound of Example 66 to give the title compound. δH (CD₃OD) 9.78(1H, s), 8.69 (1H, d, J 5.7 Hz), 7.99 (2H, d, J 8.5 Hz), 7.90 (1 H, s),7.84 (1H, d, J 5.7 Hz), 7.2 (2H, d, J 8.5 Hz), 5.30 (1H, m), 3.99 (3H,s), 3.60 (4H, br), 3.42 (1H, dd, J 14.2, 4.3 Hz), 3.11 (1H, dd, J 14.2,10.0 Hz), 1.21 (6H, t, J 7.2 Hz); m/z (ES⁺, 70V) 518 (MH⁺).

EXAMPLE 68Ethyl-(S)-3-{(4-[(trifluoromethyl)-2,7-naphthyridin-1-yl]oxy)phenyl}-2-[2-ethoxy-3,4-dioxocyclobut-1-enylamino]propanoate

[0289] HCl gas was bubbled through a solution of Intermediate 18 (298mg, 0.57 mmol) in EtOAc (5 ml) for 10 min. The solvent was removed invacuo, the residue taken up in EtOH (7 ml) and to the suspension wasadded DIPEA (2.11 mg, 1.71 mmol) followed by1,2-diethoxy-3,4-dioxocyclobut-1-ene (102 mg, 0.60 mmol). After 2.5 hthe solvent was removed and the residue purified by chromatography(SiO₂; 60% EtOAc/Hexane to give the title compound (272 mg, 90%) as anoff-white glass. δH (CD₃OD) 9.66 (1H, s), 9.74 (1H, d, J 5.8 Hz), 7.87(1H, d, J 5.7 Hz), 7.82 (1H, s), 7.23 (2H, d, J 8.7 Hz), 7.17 (2H, m),4.94,4.57 (1H, 2 x m), 4.55 (2H, m), 4.10 (2H, q, J 6.7 Hz), 3.20 (1H,m), 2.96 (1H, m), 1.28 (3H, m), 1.15 (3H, t, J 7.5 Hz); m/z (ES⁺, 70V)530 (MH⁺).

EXAMPLE 69Ethyl-(S)-3-{1(4-[(3-trifluoromethyl)-2,7-naphthyridin-1-yloxy)phenyl}-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoate

[0290] To the compound of Example 68 (135 mg, 0.26 mmol) in EtOH (2.5ml) and DCM (1.5 ml) was added diethylamine (56 mg, 0.77 mmol). After 2days the solvent was removed and the residue purified by chromatography(SiO₂: EtOAc) to give the title compound (142 mg, 100%) as a colorlessglass. δH (CD₃OD) 9.82 (1H, s), 8.89 (1H, d, J 5.8 Hz), 8.03 (1H, d, J5.8 Hz), 7.98 (1H, s ), 7.42 (2H, d, J 6.7 Hz), 7.32 (2H, d, J 6.7 Hz),3.48 (1H, dd), 3.20 (1H, dd), 1.32 (4H, t, J 7.1 Hz), 1.23 (6H, t, J 7.2Hz). m/z (ES⁺, 70V) 583 (MH⁺).

EXAMPLE 70(S-3-{(4-[(3-Trifluoromethyl)-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]proanoicacid

[0291] A solution of the compound of Example 69 (128 mg. 0.22 mmol) in1:1 THF:H₂O (4 ml) was treated with LiOH.H₂O (14 mg, 0.330 mmol). After2 h solvent removed in vacuo and the residue purified by chromatography(SiO₂; DCM:MeOH:AcOH:H₂O 200:20:3:2) to give the title compound (95 mg,70%) as an off white solid. δH (DMSO-d⁶, 350K) 9.82 (1H, t, 0.7 Hz),8.98 (1H, d, J 5.7 Hz), 8.13 (1H, s ), 8.09 (1H, d, J 5.8 Hz), 7.41 (2H,d, J 8.7 Hz), 7.34 (2H, d, J 8.7 Hz), 5.17 (1H, m), 3.54 (4H, m), 3.35(1H, dd, J 14.2, 4.4 Hz), 3.18 (1H, dd, J 14.1, 9.8 Hz), 1.16 (6H, t, J7.1 Hz). m/z (ES⁺, 70V) 529 (MH⁺).

EXAMPLE 71Ethyl-(S)-3-{(4-[(3-trufluoromethyl)-2,7-naphthyridin-1-yl]oxy)phenyl}-2-[2-(azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoate

[0292] To the compound of Example 68 (135 mg, 0.26 mmol) in EtOH) (2.5ml) and DCM (1 ml) was added azepane (25 mg, 0.26 mmol). After 2 h thesolvent was removed and the residue purified by chromatography (SiO₂:EtOAc) to give the title compound (128 mg, 86%) as a colorless glass. δH(CD₃OD) 9.91 (1H, s), 8.99 (1H, d, J 5.8 Hz), 8.12 (1H, d, J 5.8 Hz),8.08 (1H, s), 7.50 (2H, d, J 8.7 Hz), 7.41 (2H, d, J 8.7 Hz), 5.45 (1H,m), 4.36 (2H, q, J 7.1 Hz), 3.98 (2H, br), 3.72 (2H, br), 3.57 (1H, dd,J 14.0, 5.0 Hz), 3.28 (1H, dd, J 14.0, 10.4 Hz), 1.85 (4H, br), 1.71(4H, br), 1.41 (3H, t, J 7.1 Hz); m/z (ES⁺, 70V), 583 (MH⁺).

EXAMPLE 72(S)-3-[(4-(3-Trifluoromethyl)-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]proanoicacid

[0293] Prepared from the compound of Example 71 in a similar manner toExample 70 to give the title compound (50 mg, 66%) as an off-whitesolid. δH (DMSO-d⁶, 350K) 9.82 (1H, t, J 0.8 Hz), 8.98 (1H, d, J 5.6Hz), 8.13 (1H, s), 8.10 (1H, d), 7.39 (2H, d, J 8.7 Hz), 7.33 (2H, d, J8.7Hz), 5.15 (1H, m), 3.68 (4H, m), 3.35 (1H, dd, J 14.2, 4.7 Hz), 3.18(1H, dd, J 14.2, 9.8 Hz), 1.69 (4H, br), 1.55 (4H, br). m/z (ES⁺, 70V)555 (MH⁺).

EXAMPLE 73(S)-3-[4-(2.7-Naphthyridin-1-ylamino]phenyl]-2-(2-morpholino-3,4-dioxocyclobut-1-enylamino)propanoicacid

[0294] A solution of the compound of Example 1 (20 mg, 0.044 mmol) inmethanol (0.2 ml) was treated with morpholine (0.01 1 ml, 0.12 mmol) andthe resulting mixture heated at 60° for 24 h. The mixture wasconcentrated to dryness then redissolved in anhydrous THF (1.0 ml) andtreated with polystyrene methylisocyanate resin (Argonaut Technologies,150 mg, 1.57 mmol/g, 0.24 mmol) at room temperature for 24 h. Theresulting mixture was filtered, and the resin was washed with methanol(1.0 ml). The combined filtrate was evaporated to dryness thenredissolved in THF (0.2 ml) and treated with an aqueous solution oflithium hydroxide monohydrate (0.2 ml of a solution of 100 mg in 4.0 mlwater, 0.12 mmol) at room temperature for 24 h. The reaction mixture wasquenched with glacial acetic acid (0.007 ml, 0.12 mmol), then evaporatedto dryness to give the title compound. HPLC-MS Retention time 2.45, 473(MH⁺).

EXAMPLE 74 Ethyl(S)-3-[4-(3-isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoate

[0295] The title compound was synthesised in a similar manner to thecompound of Example 42 from the product of the reaction betweenIntermediate 20 and ethyl(S)-3-(4-aminophenyl)-2-(t-butyloxycarbonylamino)propanoate. δH (CDCl₃)9.62 (1H, s ), 8.62 (1H, d, J 5.8 Hz), 7.45 (1H, d, J 5.8 Hz), 7.15 (2H,d, J 8.6 Hz), 7.12 (2H, d, J 8.6 Hz), 7.00 (1H, s), 6.27, 5.81, 5.12 and4.57 (together 1H, br m), 4.75, 4.60 (2H, m), 4.19 (2H, q, J 7.1 Hz),3.23-3.05 (2H, m), 2.48 (2H, d, J 7.1 Hz), 1.94 (1H, septet, J 6.8 Hz),1.39 (3H, t, J 7.0 Hz), 1.24 (3H, t, J 7.1 Hz) and 0.80 (6H, d, J 6.6Hz); m/z (ES⁺) 518 (MH⁺).

EXAMPLE 75 Ethyl(S)-3-[4-(3-isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoate

[0296] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 74 and azepane. δH (d⁶ DMSO) 9.56 (1H, s), 8.69(1H, d, J 5.7 Hz), 7.79 (1H, d, J 9.2 Hz), 7.75 (1H, d, J 5.7 Hz), 7.31(2H, d, J 8.5 Hz), 7.29 (1H, s), 7.20 (2H, d, J 8.5 Hz), 5.16 (1H, m),4.13 (2H, q, J 7.0 Hz), 3.80-3.40 (4H, br m), 3.27 (1H, dd, J 13.9, 4.5Hz), 3.06 (1H, dd, J 13.9, 10.7 Hz), 2.45 (2H, masked d), 1.88 (1H,septet, J 6.7 Hz), 1.68-1.50 (4H, m), 1.50-1.35(4H, m), 1.18(3H, t, J7.1 Hz)and .77(6H, d, J 6.7 Hz); m/z (ES⁺) 570 (MH⁺).

EXAMPLE 76(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoicacid

[0297] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 75. δH (d⁶ DMSO, 350K) 9.61(1H, s), 8.74 (1H, d,J 5.7 Hz), 7.77 (1H, d, J 5.7 Hz), 7.37 (1H, s), 7.33 (2H, d, J 8.6 Hz),7.28 (1H, d, J 9.0 Hz), 7.25 (2H, d, J 8.6 Hz), 5.17 (1H, narrow m),3.72-3.63 (4H, m), 3.33 (1H, dd, J 14.0, 4.2 Hz), 3.15 (1H, dd, J 14.0,9.8 Hz), 2.57 (2H, d, J 7.0 Hz), 2.01 (1H, septet, J 6.8 Hz), 1.73-1.60(4H, m), 1.60-1.50 (4H, m) and 0.87 (6H, d, J 6.8 Hz); m/z (ES⁺) 540(MH⁺).

EXAMPLE 77Ethyl(S)-3-[4-(3-isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoate

[0298] Prepared in a similar manner to the compound of Example 43 fromthe compound of Example 74 and the diethylamine. δH (d⁶ DMSO) 9.47 (1H,s), 8.60 (1H, d, J 5.7 Hz), 7.68 (1H, d, J 9.0 Hz), 7.65 (1H, d, J 5.7Hz), 7.23 (2H, d, J 8.6 Hz), 7.20 (1H, s), 7.10 (2H, d, J 8.6 Hz), 5.08(1H, m), 4.04 (2H, q, J 6.8 Hz), 3.50-3.30 (4H, m), 3.17 (1H, dd, J13.9, 4.7 Hz), 2.96 (1H, dd, J 13.9, 10.9 Hz), 2.37 (2H, d), 1.78 (1H,septet, J 6.8 Hz), 1.09 (3H, t, J 7.1 Hz), 0.98 (6H, t, J 7.1 Hz) and0.69 (6H, d, J 6.8 Hz), m/z (ES⁺) 545 (MH⁺).

EXAMPLE 78(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoicacid

[0299] Prepared in a similar manner to the compound of Example 44 fromthe compound of Example 77. 5H (d⁶ DMSO, 350K) 9.66 (1H, s), 8.77 (1H,d, J 5.7 Hz), 7.81 (1H, d, J 5.7 Hz), 7.41 (2H, d, J 8.7 Hz), 7.40 (1H,d, J 9.2 Hz), 7.37 (1H, s ), 7.30 (2H, d, J 8.7 Hz), 5.22 (1H, m),3.67-3.53 (4H, m), 3.38 (1H, dd, J 14.1, 4.5 Hz), 3.19 (1H, dd, J 14.1,1 0.1 Hz), 2.61 (2H, d, J 6.8 Hz), 2.05 (1H, septet, J 6.8 Hz), 1.21(6H, t, J 7.1 Hz) and 0.91 (6H, d, J 6.8 Hz); m/z (ES⁺) 517 (MH⁺).

EXAMPLE 79 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoate

[0300] A solution of the crude Intermediate 22 (3.2 g, 8.4 mmol),1,2-diethoxy-3,4-dioxocyclobut-1-ene (1.43 g, 8.4 mmol),N,N-diisopropylethylamine (2.71 g, 21 mmol) in MeOH (20 ml) was stirredat room temperature for 72 h. The mixture was concentrated in vacuo andpurified by chromatography (SiO₂; gradient elution EtOAc:Hexane 1:1 to9:1) to give the title compound as an orange solid, (1.44 g, 36%). δH(d⁶ DMSO, 400 MHz, 350K) 9.76 (1H, s), 9.37 (1H, s), 8.50 (1H, br s),7.95 (1H, d, J 2.0 Hz), 7.93 (3H, m), 7.37 (1H, s), 7.36 (2H, d, J 3.0Hz), 7.35 (1H, s), 5.30 (1H, br s), 4.71 (2H, q, J 7.0 Hz), 4.08 (2H,m), 3.30 (1H, m), 2.97 (1H, dd, J 11.9, 6.2 Hz), 2.5 (3H, s), 1.42 (3H,t, J 7.0 Hz) and 1.19 (3H, t, J 7.0 Hz); m/z (ES⁺, 70V) 474 (MH⁺).

EXAMPLE 80 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0301] A solution of the compound of Example 79 (300 mg, 0.63 mmol) andazepane (0.19 g, 1.89 mmol) in MeOH (10 ml) was stirred at roomtemperature overnight. The solid was isolated by filtration and dried togive the title compound as a pale yellow powder (66 mg, 18%). δH (d⁶DMSO) 9.80 (1H, s), 9.55 (1H, m), 8.55 (1H, m), 7.85 (3H, m), 7.50 (1H,m), 7.30 (2H, m), 7.00 (1H, s), 5.90 (1H, m), 4.10 (2H, m), 3.45 (4H,m), 3.25 (1H, m), 3.15 (1H, m), 2.55 (3H, s), 1.60 (4H, m), 1.40 (4H, m)and 1.20 (3H, t); m/z (ES⁺, 70V) 527 (MH⁺).

EXAMPLE 81(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid

[0302] Prepared in a similar manner to the compound of Example 40 fromthe compound of Example 80. δH (d⁶ DMSO, 350K) 9.76 (1H, s), 9.33 (1H,br s), 8.58 (1H, d, J 6.0 Hz), 7.91 (2H, d, J 9.0 Hz), 7.54 (1H, d, J9.0 Hz), 7.41 (2H, d, J 9.0 Hz), 6.97 (1H, s ), 5.75 (1H, m), 3.72 (4H,m), 2.93 (2H, m), 2.48 (3H, s), 1.58 (4H, m), 1.57 (4H, m); m/z (ES⁺,70V) 499 (MH⁺).

EXAMPLE 82 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoate

[0303] Prepared in a similar manner to the compound of Example 80 fromthe compound of Example 79 and diethylamine. δH (d⁶ DMSO, 350K) 9.76(1H, s), 9.33 (1H, br s), 8.58 (1H, d, J 5.0 Hz), 7.91 (2H, d, J 6.0Hz), 7.56 (1H, d, J 5.0 Hz), 7.42 (2H, d, J 9.0 Hz), 6.98 (1H, s), 5.78(1H, t, J 7.0 Hz), 3.59 (4H, m), 2.90 (2H, m), 2.48 (3H, s) and 1.19(6H, t, J 7.0 Hz); m/z (ES⁺, 70V) 473 (MH⁺).

EXAMPLE 83(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoicacid

[0304] Prepared in a similar manner to the compound of Example 40 fromthe compound of Example 82. δH (d⁶ DMSO, 350K) 9.75 (1H, s), 9.4 (1H,s), 8.55 (1H, d), 7.80 (2H, d), 7.70 (1H, d), 7.50 (1H, d), 7.25 (2H,d), 6.80 (1H, s), 5.75 (1H, q), 3.90 (4H, m), 3.85 (1H, m), 3.75 (1H,m), 2.30 (3H, s) and 1.00 (6H, t); m/z (ES⁺, 70V) 487 (MH⁺).

EXAMPLE 84 Ethyl(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-[2-(2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0305] Prepared in a similar manner to the compound of Example 80 fromthe compound of Example 79 and 2,5-dimethylpyrrolidine. δH (d⁶ DMSO)9.74 (1H, s), 9.29 (1H, s), 8.57 (1H, d, J 6.0 Hz), 7.92 (2H, d, J 4.0Hz), 7.53 (1H, m), 7.40 (2H, d, J 4.0 Hz), 7.35 (1H, s), 5.87 (1H, m),4.11 (2H, m), 4.09 (2H, m), 3.62 (3H, s), 3.14 (1H, m), 3.08 (1H, m),2.47 (3H, s), 1.75 (2H, m), 1.71 (2H, m), 1.31 (6H, m) and 1.19 (3H, t,J 7.0 Hz). m/z (ES⁺, 70V) 527 (MH⁺).

EXAMPLE 85(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-3-[2-(2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoate

[0306] Prepared in a similar manner to the compound of Example 40 fromthe compound of Example 84. δH (d⁶ DMSO) 9.76 (1H, s), 9.50 (1H, s),8.58 (1H, d, J 5.0 Hz), 7.89 (2H, m), 7.58 (1H, d, J 5.0 Hz), 7.39 (2H,d, J 9.0 Hz), 6.98 (1H, s ), 5.75 (1H, m), 4.20 (2H, m), 4.09 (1H, m),2.82 (2H, m), 2.44 (3H, s), 2.10 (2H, m), 1.68 (2H, m) and 1.28 (6H, d,J 6.0 Hz). m/z (ES⁺, 70V) 499 (MH⁺).

[0307] LC-MS Conditions: Lunca C18(2) 50×4.6 mm (3 um) column, running agradient of 95% [0.1% aqueous formic acid], 5% [0.1% formic acid inacetonitrile] to 5% [0.1% aqueous formic acid], 95% [0.1% formic acid inacetonitrile] over 3 min, then maintaining the mobile phase at thatratio for a further 2 min. Flow rate 1.0 m/min. MS was acquired by APIelectrospray in positive ion mode, at 80V, scanning from 120 to 1000amu.

[0308] The compounds of Examples 86-122 shown in Table 1 were preparedfrom the compound of Example 1 in a similar manner to the compound ofExample 73 using the appropriate amine in place of morpholine.

[0309] The compounds of Examples 123-129 shown in Table 2 were preparedfrom the compound of Example 30 in a similar manner to the compound ofExample 73 using the appropriate amine in place of morpholine.

[0310] In each of the Tables 1 and 2 the letter X¹ indicates the pointof attachment of the amine fragment (R¹) to the square in the structureat the head of the table. TABLE 1

HPLC Retention R1 MH+ Time (min) EXAMPLE 86

486 2.72 EXAMPLE 87

486 2.71 EXAMPLE 88

516 2.67 EXAMPLE 89

472 2.63 EXAMPLE 90

516 3.02 EXAMPLE 91

535 2.33 EXAMPLE 92

526 2.94 EXAMPLE 93

502 2.57 EXAMPLE 94

500 2.84 EXAMPLE 95

500 2.79 EXAMPLE 96

502 2.65 EXAMPLE 97

502 2.63 EXAMPLE 98

514 2.91 EXAMPLE 99

520 2.62 EXAMPLE 100

500 2.86 EXAMPLE 101

523 2.31 EXAMPLE 102

490 2.64 EXAMPLE 103

460 2.67 EXAMPLE 104

514 2.94 EXAMPLE 105

486 2.75 EXAMPLE 106

486 2.7  EXAMPLE 107

522 2.87 EXAMPLE 108

457 2.51 EXAMPLE 109

460 2.69 EXAMPLE 110

508 2.81 EXAMPLE 111

540 2.96 EXAMPLE 112

546 2.71 EXAMPLE 113

474 2.68 EXAMPLE 114

460 2.6  EXAMPLE 115

445 2.56 EXAMPLE 116

500 2.68 EXAMPLE 117

520 2.76 EXAMPLE 118

536 2.85 EXAMPLE 119

501 2.09 EXAMPLE 120

587 2.72 EXAMPLE 121

522 2.79 EXAMPLE 122

486 2.6 

[0311] TABLE 2

HPLC Retention R1 MH+ Time (min) EXAMPLE 123

515 3.26 EXAMPLE 124

535 3.36 EXAMPLE 125

551 3.56 EXAMPLE 126

516 2.39 EXAMPLE 127

602 3.28 EXAMPLE 128

491 3.00 EXAMPLE 129

537 3.43

[0312] The following assays can be used to demonstrate the potency andselectivity of the compounds according to the invention. In each ofthese assays an IC₅₀ value was determined for each test compound andrepresents the concentration of compound necessary to achieve 50%inhibition of cell adhesion where 100%=adhesion assessed in the absenceof the test compound and 0%=absorbance in wells that did not receivecells.

α₄β₁ Integrin-dependent Jurkat Cell Adhesion to VCAM-lg

[0313] 96 well NUNC plates were coated with F(ab)₂ fragment goatanti-human IgG Fcγ-specific antibody [Jackson Immuno Research109-006-098: 100 μl at 2 μg/ml in 0.1M NaHCO₃, pH 8.4], overnight at 4°.The plates were washed (3×) in phosphate-buffered saline (PBS) and thenblocked for 1 h in PBS/1% BSA at room temperature on a rocking platform.After washing (3× in PBS) 9 ng/ml of purified 2d VCAM-lg diluted inPBS/1% BSA was added and the plates left for 60 minutes at roomtemperature on a rocking platform. The plates were washed (3× in PBS)and the assay then performed at 37° for 30 min in a total volume of 200μl containing 2.5×10⁵ Jurkat cells in the presence or absence oftitrated test compounds.

[0314] Each plate was washed (2×) with medium and the adherent cellswere fixed with 100 μl methanol for 10 minutes followed by another wash.100 μl 0.25% Rose Bengal (Sigma R4507) in PBS was added for 5 minutes atroom temperature and the plates washed (3×) in PBS. 100 μl 50% (v/v)ethanol in PBS was added and the plates left for 60 min after which theabsorbance (570nm) was measured.

α₄β₇ Integrin-dependent JY Cell Adhesion to MAdCAM-lg

[0315] This assay was performed in the same manner as the α₄β₂ assayexcept that MAdCAM-lg (150 ng/ml) was used in place of 2d VCAM-lg and asub-line of the β-lympho blastoid cell-line JY was used in place ofJurkat cells. The IC₅₀ value for each test compound was determined asdescribed in the α₄β₁ integrin assay.

α₅β₁ Integrin-dependent K562 Cell Adhesion to Fibronectin

[0316] 96 well tissue culture plates were coated with human plasmafibronectin (Sigma F0895) at 5 μg/ml in phosphate-buffered saline (PBS)for 2 hr at 37° C. The plates were washed (3× in PBS) and then blockedfor 1 h in 100 μl PBS/1% BSA at room temperature on a rocking platform.The blocked plates were washed (3× in PBS) and the assay then performedat 37° C. in a total volume of 200 μl containing 2.5×10⁵ K562 cells,phorbol-12-myristate-13-acetate at 10 ng/ml, and in the presence orabsence of titrated test compounds. Incubation time was 30 minutes. Eachplate was fixed and stained as described in the α₄β₁ assay above.

α_(m)β₂-dependent Human Polymorphonuclear Neutrophils Adhesion toPlastic

[0317] 96 well tissue culture plates were coated with RPMI 1640/10% FCSfor 2 h at 37° C. 2×10⁵ freshly isolated human venous polymorphonuclearneutrophils (PMN) were added to the wells in a total volume of 200 μl inthe presence of 10 ng/ml phorbol-12-myristate-13-acetate, and in thepresence or absence of test compounds, and incubated for 20 min at 37°C. followed by 30 min at room temperature. The plates were washed inmedium and 100 μl 0.1% (w/v) HMB (hexadecyl trimethyl ammonium bromide,Sigma H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to eachwell. The plates were then left on a rocker at room temperature for 60min. Endogenous peroxidase activity was then assessed using tetramethylbenzidine (TMB) as follows. PMN lysate samples mixed with 0.22% H₂O₂(Sigma) and 50 μg/ml TMB (Boehringer Mannheim) in 0.1M sodiumacetate/citrate buffer, pH 6.0 and absorbance measured at 630 nm.

αIIb/β₃-dependent Human Platelet Aggregation

[0318] Human platelet aggregation was assessed using impedanceaggregation on the Chronolog Whole Blood Lumiaggregometer. Humanplatelet-rich plasma (PRP) was obtained by spinning fresh human venousblood anticoagulated with 0.38% (v/v) tri-sodium citrate at 220xg for 10min and diluted to a cell density of 6×10⁸/ml in autologous plasma.Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer(g/liter: NaCl 8.0; MgCl₂.H₂O 0.427; CaCl₂ 0.2; KCl 0.2; D-glucose 1.0;NaHCO₃ 1.0; NaHPO₄.2H₂O 0.065). Aggregation was monitored followingaddition of 2.5 μM ADP (Sigma) in the presence or absence of inhibitors.

[0319] In the above assays the preferred compounds of the invention inwhich R¹ is an α₄ integrin binding group, such as the compounds of theExamples generally have IC₅₀ values in the α₄β₁ and α₄β₇ assays of 1 μMand below. In the other assays featuring α integrins of other subgroupsthe same compounds had IC₅₀ values of 50 μM and above thus demonstratingthe potency and selectivity of their action against α₄ integrins.

[0320] The advantageous clearance properties of compounds according tothe invention may be demonstrated as follows:

[0321] Hepatic clearance, whether metabolic or biliary, can make asubstantial contribution to the total plasma clearance of a drug. Thetotal plasma clearance is a principal parameter of the pharmacokineticproperties of a medicine. It has a direct impact on the dose required toachieve effective plama concentrations and has a major impact on theelimination half-life and therefore the dose-interval. Furthermore, highhepatic clearance is an indicator of high first-pass hepatic clearanceafter oral administration and therefore low oral bioavailability.

[0322] Many peptidic and non-peptidic carboxylic acids of therapeuticinterest are subject to high hepatic clearance from plasma. Except fordrugs which function in the liver, hepatic uptake from blood or plasmais undesirable because it leads to high hepatic clearance if thecompound is excreted in bile or metabolised, or if the substance is notcleared from the liver, it may accumulate in the liver and interferewith the normal function of the liver.

[0323] The total plasma clearance of a compound according to theinvention can be determined as follows:

[0324] a small dose of the compound in solution is injected into a veinof a test animal. Blood samples are withdrawn from a blood vessel of theanimal at several times after the injection, and the concentration ofcompound in the bleed or plasma is measured using a suitable assay. Thearea under the curve (AUCiv) is calculated by non-compartmental methods(for example, the trapezium method) or by pharmacokinetic modelling. Thetotal plasma clearance (CL_(p)) is calculated by dividing theintravenous dose(D_(iv)) by the AUC_(iv) for the blood plasmaconcentration−time course of a drug administered by the intravenousroute:

CL _(p) =D _(iv) ÷AUC _(iv)

[0325] When tested in this manner, compounds according to the inventionare not rapidly or extensively extracted by the liver and have low totalplasma clearance where low is defined as less than 10 ml/min/kg in thelaboratory rat (Sprague Dawley CD). This compares favourably withfunctionally equivalent integrin binding compounds in which the squaricacid framework and/or the carboxylic ester or amide R group of compoundsof formula (1) is not present.

1. A compound of formula (1):

wherein Ar¹ is an optionally substituted 2,7-naphthridin-1-yl group; L²is a covalent bond or a linker atom or group; Ar2 is an optionallysubstituted aromatic or heteroaromatic chain; Alk is a chain —CH₂CH(R)—,—CH═C(R)—,

 in which R is a carboxylic acid (—CO₂H) or a derivative or biosterethereof; R¹ is a hydrogen atom or a C₁₋₆alkyl group; L¹ is a covalentbond or a linker atom or group; Alk¹ is an optionally substitutedaliphatic chain; n is zero or the integer 1; R² is a hydrogen atom or anoptionally substituted heteroaliphatic, cycloaliphatic,heterocycloaliphatic, polycycloalphatic, heteropoly-cycloaliphatic,aromatic or heteroaromatic group; and the salts, solvates, hydrates andn-oxides thereof:
 2. A compound according to claim 1 in which Alk is achain —CH₂CH(R)—, or


3. A compound according to claim 1 in which R is a carboxylic acid(—CO₂H) group.
 4. A compound according to claim 1 in which R is anesterified carboxyl group of formula —CO₂Alk⁷.
 5. A compound accordingto claim 1 in which Ar² is an optionally substituted phenylene group. 6.A compound according to claim 1 in which R¹ is a hydrogen atom.
 7. Acompound according to claim 1 in which L² is an —O— atom or —N(R8)—group.
 8. A compound according to claim 7 in which R⁸ is a hydrogen atomor a methyl group.
 9. A compound according to claim 1 in which L¹ is a—N(R⁸)— group where R⁸ is a hydrogen atom or a C₁₋₆alkyl group.
 10. Acompound according to claim 1 in which L¹ is a covalent bond and n isthe integer
 1. 11. A compound according to claim 1 in which n is theinteger 1 and Alk¹ is an optionally substituted straight or branchedC₁₋₆alkylene chain.
 12. A compound according to claim 11 in which Alk¹is a —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂— or —C(CH₃)₂CH₂— chain.13. A compound according to claim 12 in which R² is a hydrogen.
 14. Acompound according to claim 1 in which L¹ is a covalent bond and n iszero.
 15. A compound according to claim 14 in which R² is an optionallysubstituted C₅₋₇heterocycloaliphatic group.
 16. A compound according toclaim 15 in which R² is an optionally substituted piperadinyl,homopiperidinyl, heptamethyleneiminyl, pyrrolidinyl, piperazinyl,homopiperazinyl, morpholinyl or thiomorpholinyl group.
 17. A compoundaccording to claim 1 of formula (2):

wherein g is zero or the integer 1, 2, 3, 4 or 5; R¹⁶ is a hydrogen atomor an atom or group —L³(Alk²)_(t)L⁴(R⁴)_(u) in which: L³ is a covalentbond or a linker atom or group; Alk² is an aliphatic or heteroaliphaticchain; t is zero or the integer 1; L⁴ is a covalent bond or a linkeratom or group; u is the integer 1, 2 or 3; R⁴ is a hydrogen or halogenatom or a group selected from optionally substituted C₁₋₆alkyl or C₃₋₈cycloalkyl, —OR⁵ [where R⁵ is a hydrogen atom, an optionally substituedC₁₋₆alkyl or C₃₋₈ cycloalkyl group], —SR⁵, —NR⁵R⁶ [where R⁶ is as justdefined for R⁵ and may be the same or different], —NO₂, —CN, —CO₂R⁵,—SO₃H, —SOR⁵, —SO₂R⁵, —SO₃R⁵, —OCO₂R⁵, —CONR⁵R⁶, —OCONR⁵R⁶, —CSNR⁵R⁶,—COR⁵, —OCOR⁵, —N(R⁵)COR⁶, —N(R⁵)CSR⁶, —SO₂N(R⁵)(R⁶), —N(R⁵)SO₂R⁶,N(R⁵)CON(R⁶)(R⁷) [where R⁷ is a hydrogen atom, an optionally substitutedC₁₋₆alkyl or C₃₋₈cycloalkyl group], —N(R⁵)CSN(R⁶)(R⁷) or—N(R⁵)SO₂N(R⁶)(R⁷), provided that when t is zero and each of L³ and L⁴is a covalent bond then u is the integer 1 and R⁴ is other than ahydrogen atom; R^(17a) and R_(17b) is each an atom or group as hereindefined for R¹⁶; and the salts, solvates, hydrates and n-oxides thereof.18. A compound which is:(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid; (S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid; (S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamnino)-3,4-dioxocyclobut-1-enylamino]propanoic acid;(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid; (S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[(2-[(2S),(5S)-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoicacid;(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(trans-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoicacid;(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1yl-3,4-dioxocyclobut-1-enylamino)propanoicacid;(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoicacid; and the salts, solvates, hydrates, N-oxides and carboxylic acidester, particularly methyl, ethyl, propyl and i-propyl esters thereof.19. A pharmaceutical composition comprising a compound according toclaim 1 together with one or more pharmaceutically acceptable carriers,excipients or diluents.